Substituted pyrazoles

ABSTRACT

Substituted pyrazoles, methods of manufacturing them, compositions containing them, and methods of using them to treat, for example, autoimmune diseases mediated by cathepsin S are described.

RELATED APPLICATIONS

[0001] This application is a division of U.S. application Ser. No.09/927,188, filed on Aug. 10, 2001, which claims priority to U.S.Application Ser. No. 60/225,178, filed on Aug. 14, 2000, the contents ofall of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention relates to a series of substituted pyrazoles,pharmaceutical compositions containing these compounds, andintermediates used in their manufacture, and methods of using them.

BACKGROUND OF THE INVENTION

[0003] Cathepsin S (EC 3.4.22.27) is a cysteine protease of the papainfamily found primarily in lysosomes (Bromme, D.; McGrath, M. E. HighLevel Expression and Crystallization of Recombinant Human Cathepsin S.Protein Science 1996, 5, 789-791).

[0004] The role of cathepsin S in the immune response is anticipated byits tissue distribution: cathepsin S is found primarily in lymphatictissues, lymph nodes, the spleen, B lymphocytes, and macrophages(Kirschke, H. Chapter 211. Cathepsin S. In Handbook of ProteolyticEnzymes. Barrett, A. J.; Rawlings, N. D.; Woessner, J. F., Eds. SanDiego: Academic Press, 1998. pp. 621-624.). Cathepsin S inhibitors havebeen shown in animal models to modulate antigen presentation and areeffective in an animal model of asthma (Riese, R. J.; Mitchell, R. N.;Villadangos, J. A.; Shi, G.-P.; Palmer, J. T.; Karp, E. R.; De Sanctis,G. T.; Ploegh, H. L.; Chapman, H. A. Cathepsin S Activity RegulatesAntigen Presentation and Immunity. J. Clin. Invest. 1998, 101, 2351-2363and Shi, G.-P.; Villadangos, J. A.; Dranoff, G.; Small, C.; Gu, L.;Haley, K. J.; Riese, R.; Ploegh, H. L.; Chapman, H. A. Cathepsin SRequired for Normal MHC Class II Peptide Loading and Germinal CenterDevelopment. Immunity 1999, 10, 197-206.).

[0005] Mice in which the gene encoding cathepsin S has been knocked outare less susceptible to collagen-induced arthritis and their immunesystems have an impaired ability to respond to antigens (Nakagawa, T.Y.; Brissette, W. H.; Lira, P. D.; Griffiths, R. J.; Petrushova, N.;Stock, J.; McNeish, J. D.; Eastman, S. E.; Howard, E. D.; Clarke, S. R.M.; Rosloniec, E. F.; Elliott, E. A.; Rudensky, A. Y. Impaired InvariantChain Degradation and Antigen Presentation and DiminishedCollagen-induced Arthritis in Cathepsin S Null Mice. Immunity 1999, 10,207-217).

[0006] These data demonstrate that compounds that inhibit theproteolytic activity of human cathepsin S should find utility in thetreatment of chronic autoimmune diseases including, but not limited to,lupus, rheumatoid arthritis, and asthma; and have potential utility inmodulating the immune response to tissue transplantation.

[0007] There are a number of cathepsin S inhibitors reported in theliterature. The most important patents are listed below.

[0008] Certain dipeptidyl nitrites are claimed by Novartis as cathepsinS inhibitors in: Altmann, et. al. WO-99/24460.

[0009] Dipeptidyl vinyl sulfones are claimed by Arris (now Axys) ascysteine protease (including cathepsin S) inhibitors in: Palmer, et. al.U.S. Pat. No. 5,976,858.

[0010] Certain peptidyl sulfonamides are claimed by Arris/Axys ascysteine protease (including cathepsin S) inhibitors in: Palmer, et. al.U.S. Pat. No. 5,776,718 (assigned to Arris, now Axys) & Klaus, et. al.U.S. Pat. No. 6,030,946 (assigned to Axys).

[0011] Compounds somewhat similar to those of the present invention aredescribed in the following references.

[0012] Winters, et. al. (Winters, G.; Sala, A.; Barone, D.; Baldoli, E.J. Med. Chem. 1985, 28, 934-940; Singh, P.; Sharma, R. C. Quant.Struct.-Act. Relat. 1990, 9, 29-32; Winters, G.; Sala, A.; Barone, D. inU.S. Pat. No. 4,500,525 (1985)) have described bicyclic pyrazoles of thetype shown below. R never contains a heterocyclic ring and no proteaseinhibitor activity is ascribed to these molecules; they are described asα1-adrenergic receptor modulators.

[0013] Shutske, et. al. Claim the bicylic pyrazoles below. The pyridinering is aromatic in their system (Shutske, G. M.; Kapples, K. J.; Tomer,J. D. U.S. Pat. No. 5,264,576 (1993)). Although reference is made to Rbeing a linker to a heterocycle, the claims specify only R=hydrogen. Thecompounds are referred to as serotonin reuptake inhibitors.

[0014] The compound2-[4-[4-(3-methyl-5-phenyl-1H-pyrazol-1-yl)butyl]-1-piperazinyl]-pyrimidineis known from EP-382637, which describes pyrimidines having anxiolyticproperties. This compound and analogs are further described in EP-502786as cardiovascular and central nervous system agents. Pharmaceuticalformulations with such compounds are disclosed in EP-655248 for use inthe treatment of gastric secreation and as anti-ulcer agents. WO-9721439describes medicaments with such compounds for treatingobsessive-compulsive disorders, sleep apnea, sexual dysfunctions, emesisand motion sickness.

[0015] The compounds5-methyl-3-phenyl-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole and5-bromo-3-(2-chlorophenyl)-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole,in particular the hydrochloride salts thereof, are known from WO-9853940and CA 122:314528, where these and similar compounds are described askinase inhibitors in the former reference and possessing affinity forbenzodiazepine receptors in the latter reference.

SUMMARY OF THE INVENTION

[0016] The present invention concerns compounds which can be representedby formula (I):

[0017] wherein:

[0018] the dashed line adjacent C—R⁶ is absent or an sp² bond;

[0019] Y is nitrogen or R²⁰C;

[0020] Z is nitrogen or R²¹ C;

[0021] T is nitrogen or R²C;

[0022] S is nitrogen or R³C;

[0023]  provided between 0 and 3 of S, T, Y, and Z are nitrogen; andfurther provided that one of S, T, Y, and Z can be ═N⁺—O⁻ where theremaining three are not nitrogen;

[0024] R²⁰ is selected from hydrogen, halogen, C₁₋₅ alkoxy, hydroxy,C₁₋₅ alkyl, cyano, nitro, C₁₋₅ haloalkyl, R^(o)R^(p)N, R^(o)R^(p)NC═O,C₂₋₈ acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C₁₋₅alkylene, phenyl, (phenyl)C₁₋₅ alkylene, R¹⁴C═O, R¹⁴S, R¹⁴SO, andR¹⁴SO₂;

[0025] R²¹ is selected from hydrogen, halogen, C₁₋₅ alkoxy, hydroxy,C₁₋₅ alkyl, cyano, nitro, C₁₋₅ haloalkyl, R^(c)R^(d)N, R^(c)R^(d)NC═O,C₂₋₈ acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C₁₋₅alkylene, phenyl, (phenyl)C₁₋₅ alkylene, R¹⁵OC═O, R¹⁵S, R¹⁵SO, andR¹⁵SO₂;

[0026] R² is selected from hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅alkyl, cyano, nitro, C₁₋₅ haloalkyl, R^(e)R^(f)N, R^(e)R^(f)NC═O, C₂₋₈acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C₁₋₅alkylene, phenyl, (phenyl)C₁₋₅ alkylene, R¹⁶OC═O, R¹⁶S, R¹⁶SO, andR¹⁶SO₂;

[0027] R³ is selected from hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅alkyl, cyano, nitro, C₁₋₅ haloalkyl, R^(g)R^(h)N, C₂₋₈ acyl, 4-7membered heterocyclyl, (4-7 membered heterocyclyl)-C₁₋₅ alkylene,phenyl, (phenyl)C₁₋₅ alkylene, R¹⁷OC═O, R^(m)R^(n)NC═O, R^(m)R^(n)NSO₂,R¹⁷S, R¹⁷SO, and R¹⁷SO₂;

[0028] R⁵ and R⁶ are independently selected from hydrogen and C₁₋₅alkyl;

[0029] R⁷ and R⁸ independently are hydrogen, C₁₋₅ alkyl, C₁₋₅ alkenyl,C₁₋₅ alkoxy, C₁₋₅ alkylthio, halogen, or 4-7 membered carbocyclyl orheterocyclyl; alternatively, R⁷ and R⁸ can be taken together to form anoptionally substituted 5- to 7-membered carbocyclic or heterocyclicring, which ring may be unsaturated or aromatic; said ring beingoptionally substituted with between 1 and 3 substituents independentlyselected from halo, hydroxy, cyano, nitro, amino, R^(t), R^(t)O—,R^(t)S—, R^(t)O(C₁₋₅ alkylene)-, R^(t)O(C═O)—, R^(t)(C═O)—, R^(t)(C═S)—,R^(t)(C═O)O—, R^(t)O(C═O)(C═O)—, R^(t)SO₂, NHR^(u)(C═NH)—, NHR^(u)SO₂—,and NHR^(u)(C═O)—;

[0030] R^(t) is C₁₋₆ alkyl, phenyl, benzyl, phenethyl, or C₂₋₅heterocyclyl, (C₁₋₅ heterocyclyl)C₁₋₆ alkylene, NH₂, mono- or di(C₁₋₆alkyl)N—, or R⁴⁹OR⁵⁰—, wherein R⁴⁹ is H, C₁₋₅ alkyl, C₂₋₅ alkenyl,phenyl, benzyl, phenethyl, C₁₋₅ heterocyclyl, or (C₁₋₅ heterocyclyl)C₁₋₆alkylene and R⁵⁰ is C₁₋₅ alkylene, phenylene, or divalent C₁₋₅heterocyclyl; and

[0031] R^(u) can be H in addition to the values for R^(t);

[0032] R^(c) is hydrogen, C₁₋₅ alkyl, phenyl, C₂₋₅ heterocyclyl, C₂₋₈acyl, aroyl, R¹⁰OC═O—, R^(i)R_(j)NC═O, R¹⁰SO—, R¹⁰SO₂—, andR^(i)R_(j)NSO₂;

[0033] R^(e) is hydrogen, C₁₋₅ alkyl, phenyl, C₂₋₅ heterocyclyl, C₂₋₈acyl, aroyl, R⁴⁰OC═O, R⁴³R⁴⁴NC═O, R⁴⁰SO, R⁴⁰SO₂, and R⁴³R⁴⁴NSO₂;

[0034] R^(m) is hydrogen, C₁₋₅ alkyl, phenyl, C₂₋₅ heterocyclyl, C₂₋₈acyl, aroyl, R⁴¹OC═O, R⁴⁵R⁴⁶NC═O, R⁴¹SO, R⁴¹SO₂, and R⁴⁵R⁴⁶NSO₂;

[0035] R^(o) is hydrogen, C₁₋₅ alkyl, phenyl, C₂₋₅ heterocyclyl, C₂₋₈acyl, aroyl, R⁴²OC═O, R⁴⁷R⁴¹NC═O, R⁴²SO, R⁴²SO₂, and R⁴⁷R⁴⁸NSO₂;

[0036] each of R^(d), R^(f), R^(n), and R^(p) is independently selectedfrom hydrogen, C₁₋₅ alkyl, phenyl, and C₂₋₅ heterocyclyl; in addition,R^(c) and R^(d), R^(e) and R^(f), R^(m) and R^(n), or R^(o) and R^(p),independently, can be taken together to form an optionally substituted4- to 7-membered heterocyclic ring, which ring may be saturated,unsaturated or aromatic;

[0037] each of R⁹, R¹⁰, R¹¹, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R⁴⁰, R⁴¹, and R⁴² isindependently C₁₋₅ alkyl, phenyl, or C₂₋₅ heterocyclyl;

[0038] each of R^(i) and R^(j), R^(k) and R^(l), R⁴³ and R⁴⁴, R⁴⁵ andR⁴⁶, R⁴⁷ and R⁴⁸ are independently hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl,phenyl, or C₂₋₅ heterocyclyl; in addition, R^(i) and R^(j), and R^(k)and R^(l), R⁴³ and R⁴⁴, R⁴⁵ and R⁴⁶, and R⁴⁷ and R⁴⁸, independently, canbe taken together to form an optionally substituted 4- to 7-memberedheterocyclic ring, which ring may be saturated, unsaturated or aromatic;

[0039] R^(g) is hydrogen, C₁₋₅ alkyl, phenyl, or C₂₋₅ heterocyclyl, C₂₋₈acyl, aroyl, R⁹OC═O, R¹⁸R¹⁹NC═O, R⁹SO, R⁹SO₂, or R¹⁸R¹⁹NSO₂;

[0040] R^(h) is hydrogen, C₁₋₅ alkyl, phenyl, or C₂₋₅ heterocyclyl;

[0041]  alternatively, R^(g) and R^(h) can be taken together to form anoptionally substituted 4- to 7-membered heterocyclic ring, which ringmay be saturated, unsaturated or aromatic;

[0042] R¹⁸ and R¹⁹ independently are hydrogen, C₁₋₅ alkyl, phenyl, orC₂₋₅ heterocyclyl;

[0043]  alternatively, R¹⁸ and R¹⁹ can be taken together to form anoptionally substituted 4- to 7-membered heterocyclic ring, which ringmay be saturated, unsaturated or aromatic;

[0044] n is 0, 1 or 2;

[0045] G is C₃₋₆ alkenediyl or C₃₋₆ alkanediyl, optionally substitutedwith hydroxy, halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, oxo, hydroximino,CO₂R^(k), NR^(k)R^(l), (L)—C₁₋₄ alkylene-, R^(k)R^(l)NCO₂, [(L)—C₁₋₅alkylene]amino, N₃, or (L)—C₁₋₅ alkoxy;

[0046] L is amino, mono- or di-C₁₋₅ alkylamino, pyrrolidinyl,morpholinyl, piperidinyl, homopiperidinyl, or piperazinyl, whereinavailable ring nitrogens can be optionally substituted with C₁₋₅ alkyl,benzyl, C₂₋₅ acyl, C₁₋₅ alkylsulfonyl, or C₁₋₅ alkoxycarbonyl;

[0047] Ar represents a monocyclic or bicyclic aryl or heteroaryl ring,optionally substituted with between 1 and 3 substituents independentlyselected from halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, C₂₋₅ alkenyl, cyano,azido, nitro, R²²R²³N, R²²S, R²²SO, R²²SO₂, R²²OC═O R²²R²³NC═O, C₁₋₅haloalkyl, C₁₋₅ haloalkoxy, C₁₋₅ haloalkylthio, and C₁₋₅ alkylthio;

[0048] R²² is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, C₂₋₅heterocyclyl, C₂-8 acyl, aroyl, R¹¹OC═O, R²⁴R²⁵NC═O, R¹¹S, R¹¹SO,R¹¹SO₂, or R²⁴R²NSO₂;

[0049] R²³ is hydrogen, C₁₋₅ alkyl, phenyl, benzyl, or C₂₋₅heterocyclyl;

[0050]  alternatively, R²² and R²³ can be taken together to form anoptionally substituted 4- to 7-membered heterocyclic ring, which ringmay be saturated, unsaturated or aromatic;

[0051] R²⁴ and R²⁵ are independently hydrogen, C₁₋₅ alkyl, phenyl,benzyl, or C₁₋₅ heteroaryl;

[0052]  alternatively, R²⁴ and R²⁵ can be taken together to form anoptionally substituted 4- to 7-membered carbocyclic or heterocyclicring, which ring may be saturated, unsaturated or aromatic;

[0053] R³² is hydrogen, C₁₋₅ alkyl, cyano, C₁₋₅ hydroxyalkyl, C₂₋₈ acyl,—(C═O)NR^(v)R^(x), CHO, or C₁₋₆ alkoxycarbonyl, wherein each of R^(v)and R^(x) is independently selected from H, C₁₋₅ alkyl, C₁₋₅hydroxyalkyl, C₁₋₅ heterocyclyl, (C₁₋₅ heterocyclyl) C₁₋₅ alkylene, C₁₅aminoalkylene, C₃₋₈ acyloxy, CHO, C₁₋₆ alkoxycarbonyl, and cyano;

[0054] Q is NR, S, or O;

[0055] R³³ represents hydrogen, C₁₋₅ alkyl, phenyl, benzyl, phenethyl,C₂₋₅ heterocyclyl, (C₂₋₅ heterocyclyl)C₁₋₅ alkylene, C₂₋₈ acyl, aroyl,R³⁵OC═O, R³⁶R³⁷NC═O, R³⁵SO, R³⁵S, R³⁵SO₂ and R³⁶R³⁷NSO₂;

[0056] R³⁵ is selected from hydrogen, C₁₋₅ alkyl, phenyl, benzyl,phenethyl, and C₂₋₅ heteroaryl;

[0057] R³⁶ and R³⁷ are each independently selected from hydrogen, C₁₋₅alkyl, phenyl, or C₂₋₅ heteroaryl;

[0058]  alternatively, R³⁶ and R³⁷ can be taken together to form anoptionally substituted 4- to 7-membered ring heterocyclic ring, whichring may be saturated, unsaturated or aromatic;

[0059] wherein each of the above hydrocarbyl or heterocarbyl groups,unless otherwise indicated, and in addition to any specifiedsubstituents, is optionally and independently substituted with between 1and 3 substituents selected from methyl, halomethyl, hydroxymethyl,halo, hydroxy, amino, nitro, cyano, C₁₋₅ alkyl, C₁₋₅ alkoxy, —COOH, C₂₋₆acyl, [di(C₁₋₄ alkyl)amino]C₂₋₅ alkylene, [di(C₁₋₄ alkyl)amino] C₂₋₅alkyl-NH—CO—, and C₁₋₅ haloalkoxy;

[0060] or a pharmaceutically acceptable salt, amide, or ester thereof;or a stereoisomeric form thereof.

[0061] The disclosed compounds are high-affinity inhibitors of theproteolytic activity of human cathepsin S. For use in medicine, thepreparation of pharmaceutically acceptable salts of compounds of formula(I) may be desirable.

[0062] Certain compounds of the present invention may have onestereogenic atom and may exist as two enantiomers. Certain compounds ofthe present invention may have two or more stereogenic atoms and mayfurther exist as diastereomers. It is to be understood by those skilledin the art that all such stereoisomers and mixtures thereof in anyproportion are encompassed within the scope of the present invention.

[0063] Another aspect of the invention provides pharmaceuticalcompositions comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier. A further embodiment of the invention is a processfor making a pharmaceutical composition comprising mixing a disclosedcompound as described above, with a suitable pharmaceutically acceptablecarrier.

[0064] The invention also contemplates pharmaceutical compositionscomprising more than one compound of formula (I) and compositionscomprising a compound of formula (I) and another pharmaceutically activeagent.

[0065] The invention features a method of treating disorders orconditions mediated by the cathepsin S enzyme, in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of any of the compounds or pharmaceutical compositionsdescribed above. If more than one active agent is administered, thetherapeutically effective amount may be a jointly effective amount. Thecompounds described herein inhibit the protease activity of humancathepsin S, an enzyme involved in the immune response. In preferredembodiments, cathepsin S inhibition is selective. As such, the disclosedcompounds and compositions are useful in the prevention, inhibition, ortreatment of autoimmune diseases such as lupus, rheumatoid arthritis,and asthma, and for the prevention, inhibition, or treatment of tissuetransplant rejection.

[0066] Additional features and advantages of the invention will becomeapparent from the detailed description below, including examples, andthe appended claims.

DETAILED DESCRIPTION OF THE INVENTION

[0067] The invention features pyrazole compounds of formula (I), methodsof making them, compositions containing them, and methods of using themto treat diseases and conditions, including those mediated by CathepsinS.

[0068] A. Terms

[0069] The following terms are defined below and by their usagethroughout this disclosure.

[0070] “Alkyl” includes optionally substituted straight chain andbranched hydrocarbons with at least one hydrogen removed to form aradical group. Alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl,hexyl, heptyl, octyl, and so on. Alkyl includes cycloalkyl, such ascyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0071] “Alkenyl” includes optionally substituted straight chain andbranched hydrocarbon radicals as above with at least one carbon-carbondouble bond (sp²). Alkenyls include ethenyl (or vinyl), prop-1-enyl,prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl,but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkenylincludes cycloalkenyl. Cis and trans or (E) and (Z) forms are includedwithin the invention.

[0072] “Alkynyl” includes optionally substituted straight chain andbranched hydrocarbon radicals as above with at least one carbon-carbontriple bond (sp). Alkynyls include ethynyl, propynyls, butynyls, andpentynyls. Hydrocarbon radicals having a mixture of double bonds andtriple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein.Alkynyl does not include cycloalkynyl.

[0073] “Alkoxy” includes an optionally substituted straight chain orbranched alkyl group with a terminal oxygen linking the alkyl group tothe rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy,isopropoxy, butoxy, t-butoxy, pentoxy and so on. “Aminoalkyl”,“thioalkyl”, and “sulfonylalkyl” are analogous to alkoxy, replacing theterminal oxygen atom of alkoxy with, respectively, NH (or NR), S, andSO₂. Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl, and so on.

[0074] “Aryl” includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl,and so on, any of which may be optionally substituted. Aryl alsoincludes arylalkyl groups such as benzyl, phenethyl, and phenylpropyl.Aryl includes a ring system containing an optionally substituted6-membered carbocyclic aromatic ring, said system may be bicyclic,bridge, and/or fused. The system may include rings that are aromatic, orpartially or completely saturated. Examples of ring systems includeindenyl, pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl,benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on.

[0075] “Heterocyclyl” includes optionally substituted aromatic andnonaromatic rings having carbon atoms and at least one heteroatom (O, S,N) or heteroatom moiety (SO₂, CO, CONH, COO) in the ring. Unlessotherwise indicated, a heterocyclic radical may have a valenceconnecting it to the rest of the molecule through a carbon atom, such as3-furyl or 2-imidazolyl, or through a heteroatom, such as N-piperidyl or1-pyrazolyl. Preferably a monocyclic heterocyclyl has between 4 and 7ring atoms, or between 5 and 6 ring atoms; there may be between 1 and 5heteroatoms or heteroatom moieties in the ring, and preferably between 1and 3. A heterocyclyl may be saturated, unsaturated, aromatic (e.g.,heteroaryl), nonaromatic, or fused.

[0076] Heterocyclyl also includes fused, e.g., bicyclic, rings, such asthose optionally condensed with an optionally substituted carbocyclic orheterocyclic five- or six-membered aromatic ring. For example,“heteroaryl” includes an optionally substituted six-memberedheteroaromatic ring containing 1, 2 or 3 nitrogen atoms condensed withan optionally substituted five- or six-memebered carbocyclic orheterocyclic aromatic ring. Said heterocyclic five- or six-memberedaromatic ring condensed with the said five- or six-membered aromaticring may contain 1, 2 or 3 nitrogen atoms where it is a six-memberedring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfurwhere it is a five-membered ring.

[0077] Examples of heterocyclyls include thiazoylyl, furyl, pyranyl,isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl,pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. Forexample, preferred heterocyclyls or heterocyclic radicals includemorpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino,cycloheptylimino, and more preferably, piperidyl.

[0078] Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl,imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzothiazolyl.

[0079] “Acyl” refers to a carbonyl moiety attached to either a hydrogenatom (i.e., a formyl group) or to an optionally substituted alkyl oralkenyl chain, or heterocyclyl.

[0080] “Halo” or “halogen” includes fluoro, chloro, bromo, and iodo, andpreferably chloro or bromo as a substituent.

[0081] “Alkanediyl” or “alkylene” represents straight or branched chainoptionally substituted bivalent alkane radicals such as, for example,methylene, ethylene, propylene, butylene, pentylene or hexylene.

[0082] “Alkenediyl” represents, analogous to the above, straight orbranched chain optionally substituted bivalent alkene radicals such as,for example, propenylene, butenylene, pentenylene or hexenylene. In suchradicals, the carbon atom linking a nitrogen preferably should not beunsaturated.

[0083] “Aroyl” refers to a carbonyl moiety attached to an optionallysubstituted aryl or heteroaryl group, wherein aryl and heteroaryl havethe definitions provided above. In particular, benzoyl isphenylcarbonyl.

[0084] As defined herein, two radicals, together with the atom(s) towhich they are attached may form an optionally substituted 4- to 7-, 5-to 7-, or a 5- to 6-membered ring carbocyclic or heterocyclic ring,which ring may be saturated, unsaturated or aromatic. Said rings may beas defined above in the Summary of the Invention section. Particularexamples of such rings are as follows in the next section.

[0085] “Pharmaceutically acceptable salts, esters, and amides” includecarboxylate salts (e.g., C₁₋₈ alkyl, cycloalkyl, aryl, heteroaryl, ornon-aromatic heterocyclic) amino acid addition salts, esters, and amideswhich are within a reasonable benefit/risk ratio, pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response. Representative saltsinclude hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactiobionate, and laurylsulfonate. These may include alkali metal andalkali earth cations such as sodium, potassium, calcium, and magnesium,as well as non-toxic ammonium, quaternary ammonium, and amine cationssuch as tetramethyl ammonium, methylamine, trimethylamine, andethylamine. See example, S. M. Berge, et al., “Pharmaceutical Salts,” J.Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference.Representative pharmaceutically acceptable amides of the inventioninclude those derived from ammonia, primary C₁₋₆ alkyl amines andsecondary di (C₁₋₆ alkyl) amines. Secondary amines include 5- or6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁₋₃ alkylprimary amines, and di (C₁₋₂ alkyl)amines. Representativepharmaceutically acceptable esters of the invention include C₁₋₇ alkyl,C₅₋₇ cycloalkyl, phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred estersinclude methyl esters.

[0086] “Patient” or “subject” includes mammals such as humans andanimals (dogs, cats, horses, rats, rabbits, mice, non-human primates) inneed of observation, experiment, treatment or prevention in connectionwith the relevant disease or condition. Preferably, the patient orsubject is a human.

[0087] “Composition” includes a product comprising the specifiedingredients in the specified amounts as well as any product whichresults directly or indirectly from combinations of the specifiedingredients in the specified amounts.

[0088] “Therapeutically effective amount” or “effective amount” meansthat amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

[0089] Concerning the various radicals in this disclosure and in theclaims, three general remarks are made. The first remark concernsvalency. As with all hydrocarbon radicals, whether saturated,unsaturated or aromatic, and whether or not cyclic, straight chain, orbranched, and also similarly with all heterocyclic radicals, eachradical includes substituted radicals of that type and monovalent,bivalent, and multivalent radicals as indicated by the context of theclaims. The context will indicate that the substituent is an alkylene orhydrocarbon radical with at least two hydrogen atoms removed (bivalent)or more hydrogen atoms removed (multivalent). An example of a bivalentradical linking two parts of the molecule is G in formula (I) whichlinks two rings.

[0090] Second, radicals or structure fragments as defined herein areunderstood to include substituted radicals or structure fragments.Hydrocarbyls include monovalent radicals containing carbon and hydrogensuch as alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whetheraromatic or unsaturated), as well as corresponding divalent radicalssuch as alkylene, alkenylene, phenylene, and so on. Heterocarbylsinclude monovalent and divalent radicals containing carbon, hydrogen,and at least one heteroatom. Examples of monovalent heterocarbylsinclude acyl, acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl,benzoyl, dialkylamino, hydroxyalkyl, and so on. Using “alkyl” as anexample, “alkyl” should be understood to include substituted alkylhaving one or more substitutions, such as between 1 and 5, 1 and 3, or 2and 4 substituents. The substituents may be the same (dihydroxy,dimethyl), similar (chlorofluoro), or different (chlorobenzyl- oraminomethyl-substituted). Examples of substituted alkyl includehaloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl,perchloromethyl, 2-bromoethyl, perfluoromethyl, and 3-iodocyclopentyl),hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl,aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and2-aminopropyl), nitroalkyl, alkylalkyl, and so on. A di(C₁₋₆ alkyl)aminogroup includes independently selected alkyl groups, to form, forexample, methylpropylamino and isopropylmethylamino, in additiondialkylamino groups having two of the same alkyl group such as dimethylamino or diethylamino.

[0091] Third, only stable compounds are intended. For example, wherethere is an NR′R″ group, and R can be an alkenyl group, the double bondis at least one carbon removed from the nitrogen to avoid enamineformation. Similarly, where a dashed line is an optional sp² bond, if itis absent, the appropriate hydrogen atom(s) is(are) included.

[0092] Preferred substitutions for Ar include methyl, methoxy,fluoromethyl, difluoromethyl, perfluoromethyl (trifluoromethyl),1-fluoroethyl, 2-fluoroethyl, ethoxy, fluoro, chloro, and bromo, andparticularly methyl, bromo, chloro, perfluoromethyl, perfluoromethoxy,methoxy, and fluoro. Preferred substitution patterns for Ar are4-substituted or 3,4-disubstituted phenyl. Compounds of the inventionare further described in the next section.

[0093] B. Compounds

[0094] The invention features compounds of formula (I) as described inthe Summary section.

[0095] Preferred compounds include those wherein:

[0096] (a) one of S, T, Y, and Z is nitrogen;

[0097] (b) S and T are CR³ and CR², respectively;

[0098] (c) S, T, Y, and Z are CR³, CR², CR²⁰, and CR²¹, respectively;

[0099] (d) (1) Z is N, Y is N, S is CR³, and T is CR²; or (2)S is N, Tis N, Y is CR²⁰, and Z is CR²¹;

[0100] (e) R² is hydrogen, halogen, C₁₋₅ alkoxy, cyano, R^(e)R^(f)N, ora 5-6 membered heterocyclyl;

[0101] (f) R³ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano,R¹⁷OC═O, or R^(g)R^(h)N, where R^(g) and R^(h) are H or C₁₋₅ alkyl, orare taken together to form a 5-6 membered heterocyclyl;

[0102] (g) each of R² and R³ is independently selected from hydrogen,halogen, and a 5-6 membered heterocyclyl;

[0103] (h) R⁵ and R⁶ are independently selected from hydrogen and C₁₋₃alkyl;

[0104] (i) one of R⁵ and R⁶ is H;

[0105] (j) R⁵ and R⁶ are each H;

[0106] (k) one of R⁷ and R⁸ is H and the other is 5-7 memberedcarbocyclyl or heterocyclyl;

[0107] (l) R⁷ and R⁸ are taken together to form an optionallysubstituted 5- to 7-membered carbocyclic or heterocyclic ring;

[0108] (m) R⁷ and R⁸ are taken together to form a six-memberedheterocyclyl;

[0109] (n) R⁷ and R⁸ taken together form a 5-7 membered heterocyclyloptionally N-substituted with R^(t)(C═O)—, R^(t)SO₂—, or NHR^(u)(C═O)—wherein R^(t) is C₁₋₆ alkyl, phenyl, or C₂₋₅ heterocyclyl and R^(u) isH, C₁₋₆ alkyl, phenyl, or C₂₋₅ heterocyclyl;

[0110] (o) each of R^(c), R^(e), R^(m), and R^(o) is independentlyselected from hydrogen, C₁₋₅ alkyl, C₂₋₈ acyl, (C₁₋₅ alkyl)OC═O, and therespective RRNC═O, RSO, RSO₂, and RRNSO₂ groups;

[0111] (p) each of R^(c), R^(d), R⁹, R^(h), R^(o), R^(f), and R^(p) isindependently selected from hydrogen and C₁₋₅ alkyl; or, independently,R^(e) and R^(f), R^(g) and R^(h), or R^(o) and R^(p) taken together forman optionally substituted 4- to 7-membered carbocyclic or heterocyclicring;

[0112] (q) R^(e) and R^(f) taken together are morpholinyl, piperidinyl,or pyrrolidinyl;

[0113] (r) each of R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R^(i), R^(j), R^(k) andR^(l) independently is hydrogen or C₁₋₅ alkyl;

[0114] (s) each of R⁹, R¹¹, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is independently C₁₋₅alkyl;

[0115] (t) R^(g) is C₁₋₅ alkyl, C₂₋₈ acyl, R⁹OC═O, R¹⁸R¹⁹NC═O, R⁹SO,R⁹SO₂, or R¹⁸R¹⁹NSO₂; and R^(h) is H or C₁₋₅ alkyl; alternatively, R^(g)and R^(h) can be taken together to form an optionally substituted 5- to6-membered heterocyclyl;

[0116] (u) R^(g) and R^(h) are each C₁₋₃ alkyl;

[0117] (v) R¹⁸ and R¹⁹ independently are hydrogen or C₁₋₅ alkyl;

[0118] (w) n is 0 or 1; or n is 1;

[0119] (x) G is C₃₋₄ alkanediyl, optionally substituted with hydroxy,halogen, [(L)—C₁₋₅ alkylene]amino, or (L)—C₁₋₅ alkyloxy;

[0120] (y) G is C₃ alkanediyl, optionally substituted with hydroxy;

[0121] (z) R²⁰ and R²¹ are independently selected from hydrogen,halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano, nitro, 4-7 memberedheterocyclyl, and R^(o)R^(p)N or R^(c)R^(d)N, respectively;

[0122] (aa) R²⁰ and R²¹ are independently selected from hydrogen,halogen, 5- to 6-membered heterocyclyl, and R^(o)R^(p)N or R^(c)R^(d)N,respectively;

[0123] (bb) Ar represents a monocyclic ring, optionally substituted with1 to 2 substituents selected from halogen, C₁₋₅ alkyl, cyano, nitro,R²²R²³ N, C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy;

[0124] (cc) Ar is a six-membered aromatic ring monosubstituted at the4-position with halogen, methyl, CF₃, or OCF₃, or disubstituted at the3- and 4-positions with substituents independently selected fromhalogen, CF₃, methyl, and OCF₃;

[0125] (dd) each of R²², R²³, and R²⁴ is independently hydrogen or C₁₋₅alkyl;

[0126] (ee) R²⁵ and R²⁶ independently are hydrogen or C₁₋₅ alkyl,

[0127]  or, alternatively, R²⁵ and R²⁶ are taken together to form anoptionally substituted 4- to 7-membered heterocyclic ring, which ringmay be saturated, unsaturated or aromatic;

[0128] (ff) R²⁵ and R²⁶ independently are hydrogen or C₁₋₅ alkyl;

[0129] (gg) Q is NR³³ or S;

[0130] (hh) Q is NR³³, R³³ is H or C₂₋₅ heterocyclyl, and R³² is H, C₁₋₅alkyl, C₁₋₅ hydroxyalkyl, —(C═O)NR^(v)R^(x), CHO, or C₁₋₆alkoxycarbonyl, wherein each of R^(v) and R^(x) is independentlyselected from H, C₁₋₅ hydroxyalkyl, (C₁₋₅ heterocyclyl)-C₁₋₅ alkylene,and C₁₋₅ aminoalkylene;

[0131] (ii) wherein Q is S and R³³ is NR³⁶R³⁷(C═O)— where each of R³⁶and R³⁷ are independently selected from hydrogen and C₁₋₅ alkyl;

[0132] (jj) R³⁵ is selected from hydrogen and C₁₋₅ alkyl; R³⁶ and R³⁷are each independently selected from hydrogen, C₁₋₅ alkyl, or,alternatively, R³⁶ and R³⁷ can be taken together to form an optionallysubstituted 4- to 7-membered heterocyclic ring;

[0133] (kk) Y is nitrogen or R²⁰C; Z is nitrogen or R²¹C; T is nitrogenor R²C; S is nitrogen or R³C; provided between 0 and 2 of S, T, Y, and Zare nitrogen; for example 1 of them is N;

[0134] (ll) R² is hydrogen, halogen, hydroxy, C₁₋₅ alkoxy, C₁₋₅ alkyl,5- to 6-membered heterocyclyl, or R^(e)R^(f)N;

[0135] (mm) R³ is hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl,5-to 6-membered heterocyclyl, or R^(g)R^(h)N;

[0136] (nn) R⁷ and R⁸ independently are taken together to form anoptionally substituted 5- to 7-membered unsaturated heterocyclic ring;

[0137] (oo) each of R^(a), R^(e), R^(m), and R^(o) is independentlyselected from hydrogen, C₁₋₅ alkyl, C₂₋₈ acyl, (C₁₋₅ alkyl)OC═O, and therespective RRNC═O, RSO, RSO₂, and RRNSO₂ groups;

[0138] (pp) each of R^(b), R^(f), R^(n), and R^(p), is independentlyselected from hydrogen and C₁₋₅ alkyl; each of R⁹, R¹¹, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R⁴⁰, R⁴¹ and R⁴² is independently C₁₋₅ alkyl; and each of R^(c),R^(d), R^(i), R^(j), R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R^(k) and R^(l) areindependently are hydrogen or C₁₋₅ alkyl;

[0139] (qq) R^(g) is hydrogen, or C₁₋₅ alkyl, C₂₋₈ acyl, R⁹OC═O,R¹⁸R¹⁹NC═O, R⁹SO, R⁹SO₂, or R¹⁸ R¹⁹NSO₂; R^(h) is hydrogen or C₁₋₅alkyl; alternatively, R^(g) and R^(h) can be taken together to form anoptionally substituted 4- to 7-membered carbocyclic or heterocyclicring, which ring may be saturated, unsaturated or aromatic; R¹⁸ and R¹⁹independently are hydrogen or C₁₋₅ alkyl; n is 0 or 1;

[0140] (rr) G is C₃₋₄ alkenediyl or C₃₋₄ alkanediyl, optionallysubstituted with hydroxy, halogen, C₁₋₅ alkyloxy, oxo, hydroximino,CO₂R^(k), R^(k)R^(l)NCO₂, or (L)—C₁₋₅ alkoxy; L is amino, mono- ordi-C₁₋₅ alkylamino, pyrrolidinyl, morpholinyl, piperidinylhomopiperidinyl, or piperazinyl, available ring nitrogens beingoptionally with C₁₋₅ alkyl, benzyl, C₂₋₅ acyl, or C₁₋₅ alkyloxycarbonyl;

[0141] (ss) R²⁰ and R²¹ are independently selected from hydrogen,halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano, nitro, and R^(o)R^(p)N;alternatively, R³ and R²⁰ or R³ and R²¹ can be taken together to form anoptionally substituted 5- or 6-membered carbocyclic or heterocyclicring, which ring may be saturated, unsaturated or aromatic; and Arrepresents a monocyclic or bicyclic aryl or heteroaryl ring, optionallysubstituted with hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano,nitro, R²²R²³ N, R²⁴SO₂, R²⁴OC═O, R²⁵R²⁶NC═O, CF₃, OCF₃, SCF₃, or C₁₋₅alkylthio; R²² is hydrogen, C₁₋₅ alkyl, phenyl, benzyl, phenethyl, C₂₋₅heteroaryl, C₂₋₈ acyl, aroyl, R²⁴OC═O, R²⁵R²⁶NC═O, R²⁴SO, R²⁴SO₂, orR²⁵R26NSO₂; R²³ is hydrogen or C₁₋₅ alkyl; alternatively, R²² and R²³can be taken together to form an optionally substituted 4- to 7-memberedcarbocyclic or heterocyclic ring, which ring may be saturated,unsaturated or aromatic; R²⁴ is hydrogen or C₁₋₅ alkyl; R²⁵ and R²⁶ areindependently hydrogen or C₁₋₅ alkyl; or, alternatively, R²⁵ and R²⁶ canbe taken together to form an optionally substituted 4- to 7-memberedcarbocyclic or heterocyclic ring, which ring may be saturated,unsaturated or aromatic;

[0142] (tt) R³² is hydrogen, C₁₋₅ alkyl, C₁₋₅ hydroxyalkyl, CHO, C₂₋₆acyl, C₁₋₆ alkoxycarbonyl, or —(C═O)NR^(v)R^(x), wherein each ofR^(v)R^(x) is independently selected from H, C₁₋₅ alkyl, C₁₋₅hydroxyalkyl, C₃₋₈ acyloxy, (amino)C₁₋₆ alkylene, (C₁₋₅heterocyclyl)C₁₋₅ alkylene, or C₁₋₆ alkoxycarbonyl; and Q is NR³³ or S;R³³ represents hydrogen, C₁₋₅ alkyl, phenyl, benzyl, (C₂₋₅heterocyclyl)C₁₋₅ alkylene, C₂₋₈ acyl, aroyl, R³⁵OC═O, R³⁶R³⁷NC═O,R³⁵SO₂ and R³⁶R³⁷NSO₂; R³⁵ is selected from hydrogen and C₁₋₅ alkyl; R³⁶and R³⁷ are each independently selected from hydrogen and C₁₋₅ alkyl;

[0143] (uu) one of R⁵ and R⁶ is H, R⁷ and R⁸ are taken together to forman optionally substituted 6-membered carbocyclic or heterocyclic ring;and Ar represents a monocyclic ring, optionally substituted with 1 to 2substituents selected from halogen, C₁₋₅ alkyl, cyano, nitro, R²²R²³N,CF₃ and OCF₃;

[0144] (vv) both R⁵ and R⁶ are each H, and

[0145] (ww) Ar is a six membered ring substituted with halogen, CF₃,methyl, halomethyl, or OCF₃, at the 3- or 4-position, or disubstitutedat the 3- and 4-positions;

[0146] (xx) R⁷ and R taken together form pyridinyl, pyrimidinyl, orpiperazinyl, optionally N-substituted with —(C═O)R^(t), SO₂—R^(t), or—(C═O)NHR^(u);

[0147] (yy) R^(e) and R^(f) taken together are independentlymorpholinyl, piperidyl, or pyrrolidinyl, optionally substituted;

[0148] (zz) the dashed line adjacent C—R⁶ is absent;

[0149] (aaa) or combinations of the above.

[0150] Specific preferred compounds include those in the Examples below,such as:1-[1-{2-Hydroxy-3-[4-(1H-indol-3-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethylphenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone;1-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol;1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-chloro-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol;1-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-chloro-2-methyl-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol;1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-methyl-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol;3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-indole-5-carbonitrile;1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-methoxy-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol;3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-indole-5-carboxylicacid ethyl ester;1-[4-(6-Chloro-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol;1-[1-(3-{4-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-2-hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone;1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-b]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol;1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol;1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-oxy-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol;1-[4-(5-Dimethylamino-1H-pyrrolo[3,2-b]pyridin-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol;1-[4-(5-Dimethylamino-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol;3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile;1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-{4-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-propan-2-ol;1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(7-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol;1-[4-(6-Fluoro-2-hydroxymethyl-benzo[b]thiophen-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol;6-Fluoro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carbaldehyde;6-Fluoro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylicacid methyl ester;6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b]thiophene-2-carboxylicacid amide; and6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b]thiophene-2-carboxylic.

[0151] Furthermore, preferred compounds include those wherein Ar isselected from 4-trifluoromethylphenyl, 4-bromophenyl, 4-chlorophenyl,4-chloro-3-methylphenyl and 3,4-dichlorophenyl.

[0152] More preferred compounds include those in Examples 4, 9, 13, and26.

[0153] Related Compounds

[0154] The invention provides the disclosed compounds and closelyrelated, pharmaceutically acceptable forms of the disclosed compounds,such as salts, esters, amides, acids, hydrates or solvated formsthereof; masked or protected forms; and racemic mixtures, orenantiomerically or optically pure forms. Related compounds also includecompounds of the invention that have been modified to be detectable,e.g., isotopically labelled with ¹⁸F for use as a probe in positronemission tomography (PET) or single-photon emission computed tomography(SPECT).

[0155] The invention also includes disclosed compounds having one ormore functional groups (e.g., hydroxyl, amino, or carboxyl) masked by aprotecting group. See, e.g., Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) ed., (1999) John Wiley & Sons, NY. Some ofthese masked or protected compounds are pharmaceutically acceptable;others will be useful as intermediates. Synthetic intermediates andprocesses disclosed herein, and minor modifications thereof, are alsowithin the scope of the invention.

[0156] Hydroxyl Protecting Groups

[0157] Protection for the hydroxyl group includes methyl ethers,substituted methyl ethers, substituted ethyl ethers, substitute benzylethers, and silyl ethers.

[0158] Substituted Methyl Ethers

[0159] Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

[0160] Substituted Ethyl Ethers

[0161] Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, andbenzyl.

[0162] Substituted Benzyl Ethers

[0163] Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyidiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(/midazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-henzodithiolan-2-yl; and benzisothiazolyl S,S-dioxido.

[0164] Silyl Ethers

[0165] Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

[0166] Esters

[0167] In addition to ethers, a hydroxyl group may be protected as anester. Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate)

[0168] Carbonates

[0169] Examples of carbonate protecting groups include methyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl,allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate,4-ethoxy-1-naphthyl, and methyl dithiocarbonate.

[0170] Assisted Cleavage

[0171] Examples of assisted cleavage include 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

[0172] Miscellaneous Esters

[0173] Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate.

[0174] Sulfonates

[0175] Examples of sulfonates include sulfate,methanesulfonate(mesylate), benzylsulfonate, and tosylate.

[0176] Amino Protecting Groups

[0177] Protection for the amino group includes carbamates, amides, andspecial —NH protective groups.

[0178] Examples of carbamates include methyl and ethyl carbamates,substituted ethyl carbamates, assisted cleavage carbamates, photolyticcleavage carbamates, urea-type derivatives, and miscellaneouscarbamates.

[0179] Carbamates

[0180] Examples of methyl and ethyl carbamates include methyl and ethyl,9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,and 4-methoxyphenacyl.

[0181] Substituted Ethyl

[0182] Examples of substituted ethyl carbamates include2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl,1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl,1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-d i-t-butylphenyl)-1-methylethyl,2-(2′- and 4′-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl,t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl,p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl,2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl anddiphenylmethyl.

[0183] Assisted Cleavage

[0184] Examples of assisted cleavage include 2-methylthioethyl,2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 2-triphenylphosphonioisopropyl,1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl,p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and2-(trifluoromethyl)-6-chromonylmethyl.

[0185] Photolytic Cleavage

[0186] Examples of photolytic cleavage include m-nitrophenyl,3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, andphenyl(o-nitrophenyl)methyl.

[0187] Urea-Type Derivatives

[0188] Examples of urea-type derivatives includephenothiazinyl-(10)-carbonyl derivative,N′-p-toluenesulfonylaminocarbonyl, and N′-phenylaminothiocarbonyl.

[0189] Miscellaneous Carbamates

[0190] Examples of miscellaneous carbamates include 1-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and2,4,6-trimethylbenzyl.

[0191] Examples of amides include:

[0192] Amides

[0193] N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl,N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl,N-p-phenylbenzoyl.

[0194] Assisted Cleavage

[0195] N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl,(N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl,N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethioninederivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and4,5-diphenyl-3-oxazolin-2-one.

[0196] Cyclic Imide Derivatives

[0197] N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and1-substituted 3,5-dinitro-4-nvridonyl

[0198] Special—NH Protective Groups

[0199] Examples of special NH protective groups include

[0200] N-Alkyl and N-Aryl Amines

[0201] N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl,N-5-dibenzosuberyl, N-triphenylmethyl,N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, andN-2-picolylamine N′-oxide.

[0202] Imine Derivatives

[0203] N-1,1-dimethylthiomethylene, N-benzylidene,N-p-methoxybenzylidene, N-diphenylmethylene,N-[(2-pyridyl)mesityl]methylene, and N—(N′,N′-dimethylaminomethylene).

[0204] Protection for the Carbonyl Group

[0205] Acyclic Acetals and Ketals

[0206] Examples of acyclic acetals and ketals include dimethyl,bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.

[0207] Cyclic Acetals and Ketals

[0208] Examples of cyclic acetals and ketals include 1,3-dioxanes,5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane,4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane,4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane,0,0′-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.

[0209] Acyclic Dithio Acetals and Ketals

[0210] Examples of acyclic dithio acetals and ketals includeS,S′-dimethyl, S,S′-diethyl, S,S′-dipropyl, S,S′-dibutyl, S,S′-dipentyl,S,S′-diphenyl, S,S′-dibenzyl and S,S′-diacetyl.

[0211] Cyclic Dithio Acetals and Ketals

[0212] Examples of cyclic dithio acetals and ketals include1,3-dithiane, 1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.

[0213] Acyclic Monothio Acetals and Ketals

[0214] Examples of acyclic monothio acetals and ketals includeO-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or —S-phenyl andO-methyl-S-2-(methylthio)ethyl.

[0215] Cyclic Monothio Acetals and Ketals

[0216] Examples of cyclic monothio acetals and ketals include1,3-oxathiolanes.

[0217] Miscellaneous Derivatives

[0218] O-Substituted Cyanohydrins

[0219] Examples of O-substituted cyanohydrins include O-acetyl,O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.

[0220] Substituted Hydrazones

[0221] Examples of substituted hydrazones include N,N-dimethyl and2,4-dinitrophenyl.

[0222] Oxime Derivatives

[0223] Examples of oxime derivatives include O-methyl, O-benzyl andO-phenylthiomethyl.

[0224] Imines

[0225] Substituted Methylene Derivatives, Cyclic Derivatives

[0226] Examples of substituted methylene and cyclic derivatives includeoxazolidines, 1-methyl-2-(1′-hydroxyalkyl)imidazoles,N,N′-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles,diethylamine adducts, and methylaluminumbis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.

[0227] Protection for the Carboxyl Group

[0228] Esters

[0229] Substituted Methyl Esters

[0230] Examples of substituted methyl esters include 9-fluorenylmethyl,methoxymethyl methylthinmethyl, tetrahydropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl,carboxamidomethyl, and N-phthalimidomethyl.

[0231] 2-Substituted Ethyl Esters

[0232] Examples of 2-substituted ethyl esters include2,2,2-trichloroethyl, 2-haloethyl, ω-chloroalkyl,2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl,2-(2′-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl,t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl,4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl,p-(methylmercapto)phenyl and benzyl.

[0233] Substituted Benzyl Esters

[0234] Examples of substituted benzyl esters include triphenylmethyl,diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl,4-picolyl and p-P-benzyl.

[0235] Silyl Esters

[0236] Examples of silyl esters include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl anddi-t-butylmethylsilyl.

[0237] Activated Esters

[0238] Examples of activated esters include thiols.

[0239] Miscellaneous Derivatives

[0240] Examples of miscellaneous derivatives include oxazoles,2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,5-alkyl-4-oxo-1,3-dioxoianes, ortho esters, phenyl group andpentaminocobalt(III) complex.

[0241] Stannyl Esters

[0242] Examples of stannyl esters include triethylstannyl andtri-n-butylstannyl.

[0243] Amides and Hydrazides

[0244] Amides

[0245] Examples of amides include N,N-dimethyl, pyrrolidinyl,piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides,N-7-nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl, andp-P-benzenesulfonamides.

[0246] Hydrazides

[0247] Examples of hydrazides include N-phenyl and N,N′-diisopropylhydrazides.

[0248] C. Synthesis

[0249] The compounds of the present invention may be prepared byconventional synthetic organic chemistry and by matrix or combinatorialmethods according to Schemes 1 to 12 below, and Examples 1 to 13. Thoseof ordinary skill in the art will be able to modify and adapt theguidance provided herein to make the disclosed compounds.

[0250] D. Formulation and Administration

[0251] The present compounds inhibit the proteolytic activity of humancathepsin S and therefore are useful as a medicine especially in methodsfor treating patients suffering from disorders or conditions which aremodulated or regulated by the inhibition of cathepsin S activity.

[0252] The invention features a method for treating a subject with acondition mediated by cathepsin S, said method comprising administeringto the subject a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of the invention. The invention alsoprovides a method for inhibiting cathepsin S activity in a subject,wherein the method comprises administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention. A third method is a method fortreating an autoimmune disease, or inhibiting the progression of anautoimmune disease, in a subject, said method comprising administeringto the subject a therapeutically effective amount of a pharmaceuticalcomposition comprising a disclosed compound. The autoimmune disease canbe, for example, lupus, rheumatoid arthritis, or preferably, asthma. Theinvention also provides a method for treating or inhibiting theprogression of tissue transplant rejection in a subject, the methodcomprising administering to the subject a therapeutically effectiveamount of a pharmaceutical composition comprising a compound of theinvention. The administration step can occur before, during, and/orafter a tissue transplant procedure.

[0253] In view of their inhibitory effect on the proteolytic activity ofhuman cathepsin S the compounds of the present invention may beformulated into various pharmaceutical forms for administrationpurposes. To prepare these pharmaceutical compositions, an effectiveamount of a particular compound, in base or acid addition salt form, asthe active ingredient is intimately mixed with a pharmaceuticallyacceptable carrier.

[0254] A carrier may take a wide variety of forms depending on the formof preparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for oral administration or parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. These include water, glycols,oils, alcohols and the like in the case of oral liquid preparations suchas suspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. In view oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are generally employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause a significant deleterious effect to the skin. Such additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid addition salts of the compounds of formula1, due to their increased water solubility over the corresponding baseform, are more suitable in the preparation of aqueous compositions.

[0255] It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification herein refers to physically discrete units suitable asunitary dosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions, teaspoonfuls, tablespoonfuls and the like, and segregatedmultiples thereof.

[0256] Pharmaceutically acceptable acid addition salts include thetherapeutically active non-toxic acid addition salt forms which thedisclosed compounds are able to form. The latter can conveniently beobtained by treating the base form with an appropriate acid. Appropriateacids comprise, for example, inorganic acids such as hydrohalic acids,e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric andthe like acids; or organic acids such as, for example, acetic,propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic,maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, palmoic and the like acids. The term addition saltalso comprises the solvates which the disclosed componds, as well as thesalts thereof, are able to form. Such solvates are for example hydrates,alcoholates and the like. Conversely the salt form can be converted bytreatment with alkali into the free base form.

[0257] Stereoisomeric forms defines all the possible isomeric formswhich the compounds of formula (I) may possess. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereochemically isomeric forms, saidmixtures containing all diastereomers and enantiomers of the basicmolecular structure. More in particular, stereogenic centers may havethe (R)— or (S)-configuration; substituents on bivalent cyclic saturatedradicals may have either the cis- or trans-configuration. The inventionencompasses stereochemically isomeric forms including diastereoisomers,as well as mixtures thereof in any proportion of the disclosedcompounds. The disclosed compounds may also exist in their tautomericforms. Such forms although not explicitly indicated in the above andfollowing formulae are intended to be included within the scope of thepresent invention.

[0258] Those of skill in the treatment of disorders or conditionsmediated by the cathepsin S enzyme could easily determine the effectivedaily amount from the test results presented hereinafter and otherinformation. In general it is contemplated that a therapeuticallyeffective dose would be from 0.001 mg/kg to 5 mg/kg body weight, morepreferably from 0.01 mg/kg to 0.5 mg/kg body weight. It may beappropriate to administer the therapeutically effective dose as two,three, four or more sub-doses at appropriate intervals throughout theday. Said sub-doses may be formulated as unit dosage forms, for example,containing 0.05 mg to 250 mg, and in particular 0.5 to 50 mg of activeingredient per unit dosage form. Examples include 2 mg, 4 mg, 7 mg, 10mg, 15 mg, 25 mg, and 35 mg dosage forms. Compounds of the invention mayalso be prepared in time-release or subcutaneous or transdermal patchformulations. Disclosed compound may also be formulated as a spray orother topical or inhalable formulations.

[0259] The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the patient may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated patient and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned herein are therefore only guidelines.

[0260] The next section includes detailed information relating to thepreparation, characterization, and use of the disclosed compounds.

E. EXAMPLES Example 1

[0261]

[0262]1-[4-(5-Chloro-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.

[0263] A. 1-Methanesulfonyl-piperidin-4-one.

[0264] Potassium carbonate (324 g, 2340 mmol) was added to a solution of4-piperidone monohydrate hydrochloride (90 g, 586 mmol) in chloroform(300 mL) and water (300 mL). The slurry was cooled to 0° C. and treatedwith methylsulfonyl chloride (136 mL, 1760 mmol) by dropwise additionover a 1 h period (gas evolution was observed). The reaction mixture wasallowed to shake for 72 h and was partitioned between CH₂Cl₂ (500 mL)and saturated aqueous NaHCO₃ (500 mL). The aqueous layer was extractedwith CH₂Cl₂ (3×200 mL). The organic layer was washed with 1% KHSO₄ (250mL), dried (Na₂SO₄), and concentrated to afford 90.5 g (87%) of a whitesolid. MS (electrospray): exact mass calculated for C₆H₁₁NO₃S, 177.1;m/z found, 178.1 [M+H]⁺. HPLC (reverse phase conditions): t_(R)=2.19min. ¹H NMR (400 MHz, CDCl₃): 3.60 (t, J=6.5 Hz, 4H), 2.89 (s, 3H), 2.59(t, J=6.3 Hz, 4H).

[0265] B.5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.

[0266] p-Toluenesulfonic acid (1.34 g, 7.0 mmol) and morpholine (25.83mL, 296 mmol) were added to a solution of1-methanesulfonyl-piperidin-4-one (50.0 g, 282 mmol) in benzene (282mL). The reaction mixture was heated in a flask equipped with acondenser and a Dean-Stark trap at reflux for 15 h. The reaction mixturewas cooled and concentrated in vacuo to give the enamine which was usedwithout further purification. The enamine was dissolved in CH₂Cl₂ (200mL) and cooled to 0° C. To this was added triethylamine (47.2 mL, 339mmol) followed by dropwise addition of 4-trifluoromethylbenzoyl chloride(42.3 mL, 285 mmol) dissolved in CH₂Cl₂ (82 mL). The reaction mixturewas allowed to warm to room temperature and stirred for 20 h. Thereaction mixture was washed with 1 N aqueous HCl (250 mL) and the CH₂Cl₂layer was separated, dried (Na₂SO₄), and concentrated. The resulting oilwas taken up in ethanol (300 mL) and treated with hydrazine (44.3 mL,1.41 mol) at 0° C. The reaction mixture was allowed to warm to roomtemperature and stirred for 24 h. The mixture was concentrated and theresulting solid was filtered with ethanol wash and dried in vacuo toafford 70 g (72%) of5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineas a white solid. MS (electrospray): exact mass calculated forC₁₄H₁₄F₃N₃O₂S, 345.0; m/z found, 346.0 [M+H]⁺. HPLC (reverse phaseconditions): t_(R)=6.33 min. ¹H NMR (400 MHz, CDCl₃): 7.72 (s, 4H), 4.58(s, 2H), 3.69 (t, J=5.7 Hz, 2H), 2.99 (t, J=5.7 Hz, 2H), 2.92 (s, 3H).

[0267] C.5-Methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.

[0268]5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(10.0 g, 29.0 mmol) and epichlorohydrin (24 mL, 307 mmol) were setstirring in DMF (150 mL) containing Cs₂CO₃ (10.4 g, 31.9 mmol). Afterstirring at room temperature for 4 days the mixture was evaporated,brought up in EtOAc and washed with water. The organics were dried(MgSO₄) and evaporated to give a light yellow solid. Columnchromatography (silica, 5% acetone/CH₂Cl₂) gave 4.1 g (35%) of a whitesolid. TLC (silica, 5% acetone/CH₂Cl₂): R_(f)=0.28. MS (electrospray):exact mass calculated for C₁₇H₁₈F₃N₃O₃S, 401.10; m/z found, 402.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃); 7.84 (d, J=8.3 Hz, 2H), 7.79 (d, J=8.3Hz, 2H), 4.70-4.62 (m, 3H), 4.25 (d, J=5.4 Hz, 1H), 3.90-3.70 (m, 2H),3.47 (m, 1H), 3.10-2.9 (m, 6H), 2.65-2.60 (m, 1H).

[0269] D.4-(5-Chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic AcidTert-butyl Ester.

[0270] 5-Chloro-1H-indole (3.2 g, 20 mmol),4-oxo-piperidine-1-carboxylic acid tert-butyl ester (7.97 g, 40 mmol)and potassium hydroxide (4.5 g, 80 mmol) were added in MeOH (40 mL) andheated to reflux for 16 h. The reaction mixture was then cooled to roomtemperature and poured into ice water (200 mL). The mixture wereextracted with 10% MeOH/CH₂Cl₂ (5×100 mL). The organic extracts wasdried over Na₂SO₄ and concentrated to form a solid. The solid was washedwith MeOH (100 mL), filtered and dried to give a light yellow solid 6.3g (94%). TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.8. MS (electrospray):exact mass calculated for C₁₈H₂₁ClN₂O₂, 332.12; m/z found, 355.0[M⁺+Na]. ¹H NMR (CDCl₃, 400 MHz): 8.26 (br s, 1H), 7.83 (d, J=1.76 Hz,1H), 7.28 (d, J=8.80 Hz, 1H), 7.19-7.14 (m, 2H), 6.09 (brs, 1H),4.15-4.10 (m, 2H), 3.66 (t, J=5.67 Hz, 2H), 2.56-2.49 (m, 2H), 1.50 (s,9H).

[0271] E. 4-(5-Chloro-1H-indol-3-yl)-piperidine-1-carboxylic AcidTert-butyl Ester.

[0272] 4-(5-Chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (6.3 g, 18.9 mmol) in EtOH (125 mL) containingPtO₂ (1 g) was placed on a Parr hydrogenator at 60 psi H₂. After 18 hthe mixture was filtered through celite and evaporated to give a whitesolid 6.0 g (94%). TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.8. MS(electrospray): exact mass calculated for C₁₈H₂₃ClN₂O₂, 334.14; m/zfound, 335.1 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz) 8.46 (br s, 1H), 7.51 (d,J=8.41 Hz, 1H), 7.32 (d, J=1.57 Hz, 1H), 7.06 (dd, J=6.46 Hz, 2.15 Hz,1H), 6.92 (d, J=2.35 Hz, 1H), 4.24 (d, J=13.11 Hz, 2H), 2.98-2.84 (m,3H), 2.00 (d, J=12.72 Hz, 2H), 1.69-1.55 (m, 2H), 1.50 (s, 9H).

[0273] F. 5-Chloro-3-piperidin-4-yl-1H-indole.

[0274] 4-(5-Chloro-1H-indol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester (3.4 g, 10.2 mmol) was set stirring in 1:1 TFA/CH₂Cl₂.After 45 min the mixture was evaporated and the golden oil brought up inEt₂O. A solid formed and was filtered, washed with Et₂O and air dried togive 3.5 g (97%) of a white solid as a TFA salt. MS (electrospray):exact mass calculated for C₁₂H₁₅ClN₂, 234.09; m/z found, 235.1 [M⁺+H].

[0275] G.1-[4-(5-Chloro-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.

[0276] 5-Chloro-3-piperidin-4-yl-1H-indole (350 mg, 1.00 mmol) and5-methane-sulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(401 mg, 1.00 mmol) were set stirring in EtOH (20 mL) containing Et₃N(215 μL, 1.54 mmol) at 80° C. After 16 h the mixture was cooled,evaporated, brought up in CH₂Cl₂ and washed with water. The organicswere dried over Na₂SO₄ and concentrated. Column chromatography (silica,0-10% MeOH/CH₂Cl₂) provided 551 mg (88%) of a white solid. TLC (silica,10% MeOH/CH₂Cl₂): R_(f)=0.8. MS (electrospray): exact mass calculatedfor C₃₀H₃₃ClF₃N₅O₃S, 635.19; m/z found, 636.2 [M⁺+H]. ¹H NMR (CDCl₃, 400MHz): 8.82 (br s, 1H), 7.68 (d, J=8.41 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H),7.54 (brs, 1H), 7.16 (d, J=8.41 Hz, 1H), 7.03 (dd, J=7.0 Hz, 1.6 Hz,1H), 6.85 (br s, 1H), 4.43 (dd, J=25.2 Hz, 14.6 Hz, 2H), 4.30-4.05 (m,3H), 4.00-3.88 (m, 1H), 3.62-3.50 (m, 1H), 3.47-3.35 (m, 1H), 3.02-2.89(m, 2H), 2.88-2.81 (m, 2H), 2.79 (s, 3H), 2.72-2.60 (m, 1H), 2.47-2.28(m, 3H), 2.12-2.00 (m, 1H), 1.96-1.85 (m, 2H), 1.74-1.50 (m, 2H).

Example 2

[0277]

[0278]1-[4-(7-Chloro-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.

[0279] A.4-(7-Chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic AcidTert-butyl Ester.

[0280] 7-Chloro-1H-indole (3.2 g, 20 mmol),4-oxo-piperidine-1-carboxylic acid tert-butyl ester (7.97 g, 40 mmol)and potassium hydroxide (4.5 g, 80 mmol) were added in MeOH (40 mL) andheated to reflux for 16 h. The reaction mixture was then cooled to roomtemperature and poured into ice water (200 mL). The mixture wasextracted with 10% MeOH/CH₂Cl₂ (5×100 mL). The organic extracts wasdried over Na₂SO₄ and concentrated to form a solid. The solid was washedwith MeOH (100 mL), filtered and dried to give a light yellow solid 6.3g (94%). TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.8. MS (electrospray):exact mass calculated for C₁₈H₂₁ClN₂O₂, 332.12; m/z found, 355.0[M⁺+Na]. ¹H NMR (CDCl₃, 400 MHz): 8.26 (br s, 1H), 7.83 (d, J=1.76 Hz,1H), 7.28 (d, J=8.80 Hz, 1H), 7.19-7.14 (m, 2H), 6.09 (brs, 1H),4.15-4.10 (m, 2H), 3.66 (t, J=5.67 Hz, 2H), 2.56-2.49 (m, 2H), 1.50 (s,9H).

[0281] B. 4-(7-Chloro-1H-indol-3-yl)-piperidine-1-carboxylic AcidTert-butyl Ester.

[0282] 4-(7-Chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (6.3 g, 18.9 mmol) in EtOH (125 mL) containingPtO₂ (1 g) was placed on a Parr hydrogenator at 60 psi H₂. After 18 hthe mixture was filtered through celite and evaporated to give a whitesolid 6.0 g (94%). TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.8. MS(electrospray): exact mass calculated for C₁₈H₂₃ClN₂O₂, 334.14; m/zfound, 335.1 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz): 8.46 (br s, 1H), 7.51 (d,J=8.41 Hz, 1H), 7.32 (d, J=1.57 Hz, 1H), 7.06 (dd, J=6.46 Hz, 2.15 Hz,1H), 6.92 (d, J=2.35 Hz, 1H), 4.24 (d, J=13.11 Hz, 2H), 2.98-2.84 (m,3H), 2.00 (d, J=12.72 Hz, 2H), 1.69-1.55 (m, 2H), 1.50 (s, 9H).

[0283] C. 7-Chloro-3-piperidin-4-yl-1H-indole.

[0284] 4-(7-Chloro-1H-indol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester (3.4 g, 10.2 mmol) was set stirring in 1:1 TFA/CH₂Cl₂.After 45 min the mixture was evaporated and the golden oil brought up inEt₂O. A solid formed and was filtered, washed with Et₂O and air dried togive 3.5 g (97%) of a white solid. MS (electrospray): exact masscalculated for C₁₂H₁₅ClN₂, 234.09; m/z found, 235.1 [M⁺+H].

[0285] D.1-[4-(7-Chloro-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.

[0286] 7-Chloro-3-piperidin-4-yl-1H-indole (341 mg, 0.97 mmol) and5-methane-sulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(130 mg, 0.32 mmol) were set stirring in EtOH (15 mL) containing Et₃N(135 μL, 0.97 mmol) at 80° C. After 16 h the mixture was cooled,evaporated, brought up in CH₂Cl₂ and washed with water. The organicswere dried over Na₂SO₄ and concentrated. Column chromatography (silica,0-10% MeOH/CH₂Cl₂) gave 120 mg (65%) of a white solid. TLC (silica, 10%MeOH/CH₂Cl₂): R_(f)=0.7. MS (electrospray): exact mass calculated forC₃₀H₃₃ClF₃N₅O₃S, 635.19; m/z found, 636.2 [M⁺+H]. ¹H NMR (CDCl₃, 400MHz): 8.55 (br s, 1H), 7.70 (d, J=8.22 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H),7.49 (d, J=9.4 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 7.00 (t, J=8.02 Hz, 1H),6.94 (br s, 1H), 4.51 (dd, J=12.5 Hz, 14.5 Hz, 2H), 4.25-4.11 (m, 3H),4.07-3.95 (m, 1H), 3.73-3.61 (m, 1H), 3.61-3.50 (m, 1H), 3.11-2.98 (m,2H), 2.88-2.85 (m, 2H), 2.83 (s, 3H), 2.82-2.72 (m, 1H), 2.55-2.38 (m,3H), 2.24-2.10 (m, 1H), 2.05-1.90 (m, 2H), 1.82-1.61 (m, 2H).

Example 3

[0287]

[0288]1-[4-(5-Chloro-2-methyl-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2

[0289] A.4-(5-Chloro-2-methyl-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicAcid Tert-butyl Ester.

[0290] 5-Chloro-2-methyl-1H-indole (3.3 g, 20 mmol),4-oxo-piperidine-1-carboxylic acid tert-butyl ester (7.97 g, 40 mmol)and potassium hydroxide (4.5 g, 80 mmol) were added in MeOH (40 mL) andheated to reflux for 16 h. The reaction mixture was then cooled to roomtemperature and poured into ice water (200 mL). The mixture wasextracted with 10% MeOH/CH₂Cl₂ (5×100 mL). The organic extracts wasdried over Na₂SO₄ and concentrated to form a solid. The solid was washedwith MeOH (100 mL), filtered and dried to give a light yellow solid 6.2g (90%). TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.8. MS (electrospray):exact mass calculated for C₁₉H₂₃ClN₂O₂, 346.14; m/z found, 347.1 [M⁺+H].

[0291] B. 4-(5-Chloro-2-methyl-1H-indol-3-yl)-piperidine-1-carboxylicAcid Tert-butyl Ester.

[0292]4-(5-Chloro-2-methyl-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (6.2 g, 17.9 mmol) in EtOH (125 mL) containingPtO₂ (1 g) was placed on a Parr hydrogenator at 60 psi H₂. After 18 hthe mixture was filtered through celite and evaporated to give a whitesolid 6.2 g (99%). TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.8. MS(electrospray): exact mass calculated for C₁₉H₂₅ClN₂O₂, 348.16; m/zfound, 349.1 [M⁺+H].

[0293] C. 5-Chloro-2-methyl-3-piperidin-4-yl-1H-indole.

[0294] 4-(5-Chloro-2-methyl-1H-indol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester (6.2 g, 107.8 mmol) was set stirring in 1:1 TFA/CH₂Cl₂.After 45 min the mixture was evaporated and the golden oil brought up inEt₂O. A solid formed and was filtered, washed with Et₂O and air dried togive 6.2 g (95%) of a white solid as a TFA salt. MS (electrospray):exact mass calculated for C₁₄H₁₇ClN₂, 248.11; m/z found, 249.1 [M⁺+H].

[0295] D.1-[4-(5-Chloro-2-methyl-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.

[0296] 5-Chloro-2-methyl-3-piperidin-4-yl-1H-indole (480 mg, 1.32 mmol)and5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(177 mg, 0.44 mmol) were set stirring in EtOH (20 mL) containing Et₃N(215 μL, 1.54 mmol) at 80° C. After 16 h the mixture was cooled,evaporated, brought up in CH₂Cl₂ and washed with water. The organicswere dried over Na₂SO₄ and concentrated. Column chromatography (silica,0-10% MeOH/CH₂Cl₂) gave 169 mg (62%) of a white solid. TLC (silica, 10%MeOH/CH₂Cl₂): R_(f)=0.6. MS (electrospray): exact mass calculated forC₃₁H₃₅ClF₃N₅O₃S, 649.21; m/z found, 650.2 [M⁺+H]. ¹H NMR (CDCl₃, 400MHz): 8.00 (s, 1H), 7.70 (d, J=8.11 Hz, 2H), 7.64 (d, J=8.41 Hz, 2H),7.57 (d, J=1.96 Hz, 1H), 7.12 (d, J=8.61 Hz, 1H), 6.99 (dd, J=6.85 Hz,1.96 Hz, 1H), 4.53 (dd, J=14.28 Hz, 12.91 Hz, 2H), 4.26-4.14 (m, 2H),4.09-3.99 (m, 1H), 3.75-3.65 (m, 1H), 3.64-3.54 (m, 1H), 3.14-3.02(m,2H), 3.00-2.89 (m, 2H), 2.86 (s, 3H), 2.76-2.63 (m, 1H), 2.54-2.45 (m,2H), 2.45-2.36 (m, 1H), 2.34 (s, 3H), 2.25-2.00 (m, 3H), 1.77-1.63 (m,2H).

Example 4

[0297]

[0298]1-{4-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.

[0299] A. 6-Chloro-3-piperidin-4-yl-1H-indole.

[0300] 6-Chloro-1H-indole (3.2 g, 20 mmol), piperidin-4-one monohydrate(6.1 g, 40 mmol) and potassium hydroxide (4.5 g, 80 mmol) were added inMeOH (40 mL) and heated to reflux for 16 h. The reaction mixture wasthen cooled to room temperature and poured into ice water (200 mL). Themixture was extracted with 10% MeOH/CH₂Cl₂ (5×100 mL). The organicextracts were dried over Na₂SO₄ and concentrated. Column chromatography(silica, 20-100% MeOH/CH₂Cl₂ with 2% NH₄OH) to obtain 5.8 9 (100%) of ayellow solid. The solid (5.8 g, 20 mmol) in EtOH (150 mL) containingPtO₂ (1 g) was placed on a Parr hydrogenator at 60 psi H₂. After 18 hthe mixture was filtered through celite and evaporated to give an offwhite solid 4.6 g (97%). MS (electrospray): exact mass calculated forC₁₃H₁₅ClN₂, 234.09; m/z found, 235.0 [M⁺+H].

[0301] B. 4-(6-Chloro-1H-indol-3-yl)-piperidine-1-carboxylic AcidTert-butyl Ester.

[0302] To a solution of 6-chloro-3-piperidin-4-yl-1 H-indole (4.6 g,19.5 mmol) in DMF (20 mL) was added di-tert-butyl dicarbonate (4.6 g,21.4 mmol). The reaction mixture was stirred at room temperature for 6h. The reaction mixture was dissolved in EtOAc (400 mL), washed withwater (3×50 mL), brine (1×50 mL). The organic layer was dried overNa₂SO₄ and concentrated. Column chromatography (silica, 20-50%EtOAc/hexanes) gave 4.2 g (64%) of the desired product. TLC (silica, 20%EtOAc/hexanes): R_(f)=0.24. MS (electrospray): exact mass calculated forC₁₈H₂₃ClN₂O₂, 334.14; m/z found, 335.1 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz)8.46 (br s, 1H), 7.42 (d, J=8.61 Hz, 1H), 7.14 (d, J=1.57 Hz, 1H), 6.96(dd, J=6.65 Hz, 1.76 Hz, 1H), 6.74 (s, 1H), 4.14 (brs, 2H), 2.89-2.70(m, 3H), 1.90 (d, J=12.13, 2H), 1.65-1.50 (m, 2H), 1.41 (s, 9H).

[0303] C.4-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylicAcid Tert-butyl Ester.

[0304] 4-(6-Chloro-1H-indol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester (2.0 g, 5.95 mmol) was dissolved in THF (30 mL). At 0°C., potassium bis(trimethylsilyl)amide (2.37 g, 11.9 mmol) was added.The reaction mixture was stirred at room temperature for 1 h.4-(2-Chloro-ethyl)-morpholine hydrochloride (1.8 g, 11.9 mmol) was addedand stirred at room temperature for an additional 1 h. The mixture wasdissolved in EtOAC (250 mL) and washed with water (2×30 mL) and brine(30 mL). The organics were dried over Na₂SO₄ and concentrated. Columnchromatography (silica, 0-5% MeOH/CH₂Cl₂) provided 2.6 g (97%) of awhite solid. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.67. MS(electrospray): exact mass calculated for C₂₄H₃₄ClN₃O₃, 447.23; m/zfound, 448.2 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz): 7.45 (d, J=8.61 Hz, 1H),7.27 (d, J=1.57 Hz, 1H), 6.99 (dd, J=6.65 Hz, 1.76 Hz, 1H), 6.84 (s,1H), 4.18 (br s, 2H), 4.06 (t, J=6.85 Hz, 2H), 3.69-3.60 (m, 4H),2.92-2.80 (m, 2H), 2.69-2.60 (m, 3H), 2.44 (t, J=4.89 Hz, 2H), 2.40 (t,J=4.30 Hz, 2H), 1.94 (d, J=12.13, 2H), 1.65-1.50 (m, 2H), 1.45 (s, 9H).

[0305] D.6-Chloro-1-(2-morpholin-4-yl-ethyl)-3-piperidin-4-yl-1H-indole.

[0306]4-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester (2.6 g, 5.81 mmol) was set stirring in 1:1TFA/CH₂Cl₂. After 45 min the mixture was evaporated and the golden oilbrought up in Et₂O. A solid formed and was filtered, washed with Et₂Oand air dried to give 2.5 g (95%) of a white solid. MS (electrospray):exact mass calculated for C₁₉H₂₆ClN₃O, 347.18; m/z found, 348.2 [M⁺+H].

[0307] E.1-[4-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidin-1-yl-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro3-c]pyridin-1-yl]-propan-2-ol.

[0308] 6-Chloro-1-(2-morpholin-4-yl-ethyl)-3-piperidin-4-yl-1H-indole(209 mg, 0.6 mmol) and5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(120 mg, 0.3 mmol) were set stirring in EtOH (20 mL) containing Et₃N (84μL, 0.6 mmol) at 80° C. After 16 h the mixture was cooled, evaporated,brought up in CH₂Cl₂ and washed with water. The organics were dried overNa₂SO₄ and concentrated. Column chromatography (silica, 0-10%MeOH/CH₂Cl₂) provided 180 mg (85%) of a white solid. TLC (silica, 10%MeOH/CH₂Cl₂): R_(f)=0.54. MS (electrospray): exact mass calculated forC₃₆H₄₄ClF₃N₆O₄S, 748.28; m/z found, 749.3 [M⁺+H]. ¹H NMR (CDCl₃, 400MHz): 7.70 (d, J=8.61 Hz, 2H), 7.64 (d, J=8.261 Hz, 2H), 7.47 (d, J=8.80Hz, 1H), 7.29 (d, J=1.96,1H), 7.02 (dd, J=6.46 Hz, 1.76 Hz, 1H), 6.81(br s, 1H), 4.54 (dd, J=4.09 Hz, 7.43 Hz, 2H), 4.24-4.14 (m, 2H),4.14-4.08 (m, 2H), 4.06-3.98 (m, 1H), 3.73-3.57 (m, 5H), 3.12-3.02 (m,2H), 2.97-2.87 (m, 2H), 2.86 (s, 3H), 2.83-2.74 (m, 1H), 2.70-2.64 (t,J=7.24 Hz, 2H), 2.54-2.42 (m, 8H), 2.23-2.14 (m, 1H), 2.05-1.96 (m, 2H),1.82-1.60 (m, 2H).

Example 5

[0309]

[0310]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

[0311] A.4-(1H-Pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicAcid Tert-butyl Ester.

[0312] A solution of 1.9 g (8.47 mmol) of 1H-pyrrolo[3,2-c]pyridine(synthesized following the procedure described in Synthesis, 1996, 882),4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 16.9 mmol)and potassium hydroxide (1.9 g, 33.9 mmol) in MeOH (20 mL) was heated toreflux for 16 h. The reaction mixture was then cooled to roomtemperature and poured into ice water (100 mL). The mixture wasextracted with 10% MeOH/CH₂Cl₂ (5×50 mL). The organic extracts was driedover Na₂SO₄ and concentrated to form a solid. The solid was washed withMeOH (50 mL), filtered and dried to give a light yellow solid 2.0 g(79%). TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.5. MS (electrospray):exact mass calculated for C₁₇H₂₁N₃O₂, 299.16; m/z found, 300.1 [M⁺+H].¹H NMR (CDCl₃, 400 MHz): 12.26 (br s, 1H), 9.20 (s, 1H), 8.28 (d, J=5.67Hz, 1H), 7.35 (dd, J=5.09 Hz, 0.78 Hz, 1H), 7.32 (s, 1H), 6.19 (br s,1H), 4.14 (br s, 2H), 3.68 (t, J=5.67 Hz, 2H), 2.61-2.55 (m, 2H), 1.48(s, 9H).

[0313] B. 4-(1H-Pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylic AcidTert-butyl Ester.

[0314]4-(1H-Pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (2 g, 6.6 mmol) in EtOH (50 mL) containing PtO₂(500 mg) was placed on a Parr hydrogenator at 60 psi H₂. After 18 h themixture was filtered through celite and evaporated to give a white solid(2.0 g, 100%). TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.49. MS(electrospray): exact mass calculated for C₁₇H₂₃N₃O₂₂, 301.18; m/zfound, 302.2 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz): 13.66 (br s, 1H), 8.88 (s,1H), 8.79 (d, J=6.46 Hz, 1H), 7.69 (d, J=6.46 Hz, 1H), 7.30 (s, 1H),4.14 (br s, 2H), 2.99-2.87 (m, 1H), 2.86-2.71 (m, 2H), 1.91 (d, J=11.54Hz, 2H), 1.64-1.50 (m, 2H), 1.38 (s, 9H).

[0315] C. 3-Piperidin-4-yl-1H-pyrrolo[3,2-c]pyridine.

[0316] 4-(1H-Pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester (2.0 g, 6.6 mmol) was set stirring in 1:1 TFA/CH₂Cl₂.After 45 min the mixture was evaporated and the golden oil brought up inEt₂O. A solid formed and was filtered, washed with Et₂O and air dried togive 2.1 g (100%) of a white solid as a TFA salt. MS (electrospray):exact mass calculated for C₁₂H₁₅N₃, 201.13; m/z found, 202.1 [M⁺+H]. ¹HNMR (CDCl₃, 400 MHz): 9.4 (br s, 1H), 8.96 (s, 1H), 8.26 (d, J=5.87 Hz,1H), 7.24 (s, 1H), 6.99 (s, 1H), 3.22-3.16 (m, 2H), 3.05-2.95 (m, 1H),2.86-2.77 (m, 2H), 2.05 (d, J=12.72 Hz, 2H), 1.89 (br s, 1H), 1.75-1.63(m, 2H).

[0317] D.1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

[0318] 3-Piperidin-4-yl-1H-pyrrolo[3,2-c]pyridine (159 mg, 0.5 mmol) and5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(200 mg, 0.5 mmol) were set stirring in EtOH (10 mL) containing Et₃N(112 μL, 0.77 mmol) at 80° C. After 16 h the mixture was cooled,evaporated, brought up in CH₂Cl₂ and washed with water. The organicswere dried over Na₂SO₄ and concentrated. Column chromatography (silica,0-10% (2 N NH₃ in MeOH)/CH₂Cl₂) provided 82 mg (27%) of a white solid.TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.8. MS (electrospray): exact masscalculated for C₂₉H₃₃F₃N₆O₃S, 602.23; m/z found, 603.2 [M⁺+H]. ¹H NMR(CDCl₃, 400 MHz): 9.62 (s, 1H), 8.90 (s, 1H), 8.21 (d, J=5.87 Hz, 1H),7.69 (d, J=7.83 Hz, 2H), 7.62 (d, J=8.41 Hz, 2H), 7.23 (d, J=5.87, 1H),6.97 (s, 1H), 4.51 (dd, J=14.48 Hz, 8.80 Hz, 2H), 4.23-4.13 (m, 2H),4.05-3.95 (m, 1H), 3.72-3.54 (m, 3H), 3.11-2.98 (m, 2H), 2.95-2.86 (m,2H), 2.84 (s, 3H), 2.51-2.39 (m, 3H), 2.20-2.11 (m, 1H), 2.07-1.97 (m,2H), 1.85-1.63 (m, 2H).

Example 6

[0319]

[0320]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

[0321] A.4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester.

[0322] 1H-Pyrrolo[2,3-b]pyridine (3 g, 25 mmol),4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.2 g, 21 mmol) andpotassium hydroxide (3.56 g, 63 mmol) were added in MeOH (60 mL) andheated to reflux for 16 h. The reaction mixture was then cooled to roomtemperature and poured into ice water (300 mL). The mixture wasextracted with 10% MeOH/CH₂Cl₂ (5×150 mL). The organic extracts wasdried over Na₂SO₄ and concentrated to form a solid. The solid was washedwith MeOH (150 mL), filtered and dried to give a light yellow solid 5.7g (91%). TLC (silica, 50% EtOAc/hexanes): R_(f)=0.3. MS (electrospray):exact mass calculated for C₁₇H₂₁N₃O₂, 299.16; m/z found, 300.2 [M⁺+H].¹H NMR (CDCl₃, 400 MHz) 10.97 (br s, 1H), 8.33 (dd, J=3.33 Hz, 1.37 Hz,1H), 8.20 (dd, J=6.65 Hz, 1.37 Hz, 1H), 7.34 (br s, 1H), 7.25 (s, 1H),7.13 (dd, J=4.89 Hz, 3.13 Hz, 1H), 4.14 (br s, 2H), 3.68 (t, J=5.28 Hz,2H), 2.56 (br s, 2H), 1.49 (s, 9H).

[0323] B. 4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester.4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1 g, 3.3 mmol) in EtOH (25 mL) containing PtO₂(250 mg) was placed on a Parr hydrogenator at 60 psi H₂. After 18 h themixture was filtered through celite and evaporated to give 0.96 g (97%)of a white solid. TLC (silica, 50% EtOAc/hexanes): R_(f)=0.5. MS(electrospray): exact mass calculated for C₁₇H₂₃N₃O₂₂, 301.18; m/zfound, 302.2 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz) 10.95 (br s, 1H), 8.26 (dd,J=3.33 Hz, 1.37 Hz, 1H), 7.96 (dd, J=6.26 Hz, 1.57 Hz, 1H), 7.11 (s,1H), 7.05 (dd, J=4.89 Hz, 3.13 Hz, 1H), 4.22 (brs, 2H), 3.00-2.79 (m,3H), 1.99 (d, J=13.89 Hz, 2H), 1.74-1.60 (m, 2H), 1.47 (s, 9H).

[0324] C. 3-Piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine.

[0325] 4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester (963 mg, 3.2 mmol) was set stirring in 1:1 TFA/CH₂Cl₂.After 45 min the mixture was evaporated and the golden oil brought up inEt₂O. A solid formed and was filtered, washed with Et₂O and air dried togive 974 mg (96%) of a white solid as a TFA salt. MS (electrospray):exact mass calculated for C₁₂H₁₅N₃, 201.13; m/z found, 202.1 [M⁺+H]. ¹HNMR (CDCl₃, 400 MHz): 8.09 (dd, J=3.33 Hz, 1.57 Hz, 1H), 7.89 (dd,J=6.26 Hz, 1.57 Hz, 1H), 7.01 (s, 1H), 6.99 (dd, J=4.89 Hz, 3.13 Hz,1H), 5.04 (brs, 2H), 3.11-3.04 (m, 2H), 2.88-2.79 (m, 1H), 2.73-2.64 (m,2H), 1.94 (d, J=12.52 Hz, 2H), 1.65-1.63 (m, 2H).

[0326] D.1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl-3-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

[0327] 3-Piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine (443 mg, 1.4 mmol) and5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(289 mg, 0.7 mmol) were set stirring in EtOH (10 mL) containing Et₃N(146 μL, mmol) at 80° C. After 16 h the mixture was cooled, evaporated,brought up in CH₂Cl₂ and washed with water. The organics were dried overNa₂SO₄ and concentrated. Column chromatography (silica, 0-10% (2 N NH₃in MeOH)/CH₂Cl₂) provided 107 mg (25%) of a white solid. TLC (silica,10% MeOH/CH₂Cl₂): R_(f)=0.45. MS (electrospray): exact mass calculatedfor C₂₉H₃₃F₃N₆O₃S, 602.23; m/z found, 603.3 [M⁺+H]. ¹H NMR (CDCl₃, 400MHz): 10.6 (br s, 1H), 8.24 (m, 1H), 7.91 (m, 1H), 7.70 (m, 2H), 7.63(m, 2H), 7.05 (br s, 1H), 7.02 (m, 1H), 4.52 (dd, J=4.28 Hz, 9.78 Hz,2H), 4.24-4.16 (m, 2H), 4.06-3.98 (m, 1H), 3.72-3.64 (m, 1H), 3.64-3.55(m, 1H), 3.11-3.00 (m, 2H), 2.96-2.87 (m, 2H), 2.85 (s, 3H), 2.82-2.74(m, 1H), 2.53-2.40 (m, 3H), 2.22-2.12 (m, 1H), 2.05-1.95 (m, 2H),1.85-1.64 (m, 2H).

Example 7

[0328]

[0329]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

[0330] A. [2-(2-Chloro-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine.

[0331] A solution of 2-chloro-4-methyl-5-nitro-pyridine (2 g, 11.59mmol) in DMF (11.6 mL) was treated with 3.08 mL (23.2 mmol, 2 eq) ofDMF-dimethylacetal and the reaction mixture was stirred at 100° C. for 4h. All volatiles were removed under reduced pressure. Columnchromatography (silica, 20% EtOAc/hexanes) provided 2.37 g (90%) of[2-(2-chloro-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine. TLC (silica,20% EtOAc/hexanes): R_(f)=0.30. MS (electrospray): exact mass calculatedfor C₉H₁₀ClN₃O₂, 227.05; m/z found, 228.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 8.79 (s, 1H), 8.02 (s, 1H), 7.35 (d, J=13 Hz, 1H), 5.94 (d, J=13Hz, 1H), 2.96 (s, 3H), 2.87 (s, 3H).

[0332] B. 5-Morpholin-4-yl-1H-pyrrolo[2,3-c]pyridine.

[0333] A solution of 450 mg (2 mmol) of[2-(2-chloro-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine in a 20 mL ofmixed solvent of MeOH—CH₂Cl₂ (1:1) was treated with 3 mL of morpholine.The reaction mixture was stirred at 65° C. for 8 h. Volatiles were thenremoved. CH₂Cl₂ (100 mL) and H₂O (30 mL) were added. The organic layerwas separated and washed with H₂O (30 mL), brine (30 mL), dried overNa₂SO₄, and concentrated. The red powder was treated with 4.0 g (63mmol, 32 eq) of ammonium formate and 10% Pd—C (120 mg). The reactionmixture was stirred at 65° C. for 30 min. The reaction mixture was thenfiltered through a pad of celite and concentrated to obtain a yellowsolid. Column chromatography (silica, 5% MeOH/CH₂Cl₂) provided 210 mg(52% for 2 steps) of 5-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridine as ayellow solid. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.40. MS(electrospray): exact mass calculated for C₁₁H₁₃N₃O, 203.11; m/z found,204.2 [M+H]⁺.

[0334] C.4-(5-Morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylicAcid Tert-butyl Ester.

[0335] A solution of 200 mg (1.0 mmol) of5-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridine and 398 mg (2.0 mmol, 2 eq)of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester in 5 mL of MeOHwas treated with 224 mg (4.0 mmol, 4 eq) of potassium hydroxide. Thereaction mixture was stirred at 65° C. for 12 h and volatiles wereremoved. The crude product was partitioned between CH₂Cl₂ (100 mL) and20 mL of H₂O. The organic layer was washed with H₂O (2×20 mL), driedover Na₂SO₄ and concentrated. The yellow powder was treated with 630 mg(10 mmol, 10 eq) of ammonium formate and 10% Pd—C (50 mg). The reactionmixture was stirred at 65° C. for 1 h. The reaction mixture was thenfiltered through a pad of celite and concentrated to obtain a yellowsolid. Column chromatography (silica, 5% MeOH/CH₂Cl₂) provided 180 mg(47% for 2 steps) of a yellow solid. TLC (silica, 5% MeOH/CH₂Cl₂):R_(f)=0.40. MS (electrospray): exact mass calculated for C₂₁H₃₀N₄O₃,386.23; m/z found, 387.2 [M+H]⁺.

[0336] D.1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

[0337]4-(5-Morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylicacid tert-butyl ester (180 mg, 0.47 mmol) was dissolved in 3.0 mL ofCH₂Cl₂ and treated with 2.5 mL of trifluoroacetic acid. The reactionmixture was stirred at 25° C. for 1 h before all volatiles were removed.The solid was dissolved in MeOH (20 mL) and neutralized with DOWEX 550AOH anion exchange resin to pH 8. The resin was then filtered off andMeOH was removed under reduced pressure. The residue was dissolved in2.5 mL of ^(i)PrOH and treated with 187 mg (0.47 mmol, 1 eq) of5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.The reaction was stirred at 85° C. for 3 h before solvent was removed.Column chromatography (silica, 5-10% MeOH/CH₂Cl₂ then 5-10% (2 N NH₃ inMeOH)/CH₂Cl₂) provided 97 mg (30%) of the title compound. TLC (silica,5% MeOH/CH₂Cl₂): R_(f)=0.25. MS (electrospray): exact mass calculatedfor C₃₃H₄₀F₃N₇O₄S, 687.28; m/z found, 688.3 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 8.47 (br s, 1H), 8.44 (d, J=1.0 Hz, 1H), 7.70 and 7.65 (ABpattern, J=8.4 Hz, 4H), 7.03 (d, J=2.1 Hz, 1H), 6.76 (s, 1H), 4.58-4.50(m, 2H), 4.21-4.00 (m, 3H), 3.90 (t, J=4.5 Hz, 4H), 3.72-3.58 (m, 2H),3.40 (t, J=4.5 Hz, 4H), 3.10-2.85 (m, 4H), 2.88 (s, 3H), 2.80-2.70 (m,1H), 2.52-2.41 (m, 3H), 2.20-2.00 (m, 3H), 1.80-1.60 (m, 2H).

Example 8

[0338]

[0339]1-[4-(6-Dimethylamino-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.

[0340] A. Dimethyl-(5-methyl-4-nitro-1-oxy-pyridin-2-yl)-amine.

[0341] A solution of 2-bromo-5-methyl-4-nitro-pyridine 1-oxide (674 mg,2.78 mmol) in 2 M dimethylamine in methanol (20 mL) was heated at 65° C.for 16 h. The solvent was evaporated under reduced pressure. The residuewas purified by column chromatography (silica, 30-80% EtOAc/hexanes) toobtain 290 mg (53%) of the desired product. TLC (silica, 50%EtOAc/hexanes): R_(f)=0.10. MS (electrospray): exact mass calculated forC₈H₁₁N₃O₃, 197.08; m/z found, 198.1 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz):8.04 (s, 1H), 7.50 (s, 1H), 3.00 (s, 6H), 2.44 (s, 3H).

[0342] B. Dimethyl-(1H-pyrrolo[3,2-c]pyridin-6-yl)-amine.

[0343] A solution ofdimethyl-(5-methyl-4-nitro-1-oxy-pyridin-2-yl)-amine (290 mg, 1.47 mmol)in DMF (3 mL) was treated with DMF-dimethylacetal (390 μL, 2.94 mmol)and the reaction mixture was stirred at 100° C. for 4 h. All volatileswere removed under reduced pressure. The red powder was treated withammonium formate (927 mg, 14.7 mmol) and 10% Pd—C (156 mg). The reactionmixture was stirred at 65° C. for 30 min. The reaction mixture was thenfiltered through a pad of celite and concentrated to obtain a yellowsolid. Column chromatography (silica, 5% MeOH/CH₂Cl₂) provided 100 mg(42% for two steps) of product as a yellow solid. TLC (silica, 10%MeOH/CH₂Cl₂): R_(f)=0.2. MS (electrospray): exact mass calculated forC₉H₁₁N₃, 161.10; m/z found, 162.1 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz): 8.55(s, 1H), 8.28 (br s, 1H), 6.96 (dd, J=1.96 Hz, 1.37 Hz, 1H), 6.45-6.43(m, 1H), 6.39 (s, 1H), 3.08 (s, 6H).

[0344] C.4-(6-Dimethylamino-1H-pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicAcid Tert-butyl Ester.

[0345] Dimethyl-(1H-pyrrolo[3,2-c]pyridin-6-yl)-amine (100 mg, 0.62mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (248 mg, 1.24mmol) and potassium hydroxide (139 mg, 2.48 mmol) were added in MeOH (5mL) and heated to reflux for 16 h. The reaction mixture was then cooledto room temperature and poured into ice water (20 mL). The mixture wasextracted with 10% MeOH/CH₂Cl₂ (5×10 mL). The organic extracts was driedover Na₂SO₄ and concentrated. The residue was purified by columnchromatography (silica, 0-5% MeOH/CH₂Cl₂) to obtain 180 mg (85%) of thetitle compound. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.58. MS(electrospray): exact mass calculated for C₁₉H₂₆N₄O₂, 342.21; m/z found,343.2 (M⁺+H). ¹H NMR (CDCl₃, 400 MHz): 9.09 (brs, 1H), 8.76 (s, 1H),6.90 (d, J=2.15 Hz, 1H), 6.32 (s, 1H), 6.10 (brs, 1H), 4.10-4.05 (m,2H), 3.62 (t, J=5.87 Hz, 2H), 3.03 (s, 6H), 2.52-2.44 (m, 2H), 1.46 (s,9H).

[0346] D.4-(6-Dimethylamino-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylicAcid Tert-butyl Ester.

[0347] A solution of4-(6-dimethylamino-1H-pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (180 mg, 0.53 mmol) in MeOH (10 mL) was treatedwith ammonium formate (332 mg, 5.3 mmol) and 10% Pd—C (56 mg). Thereaction mixture was stirred at 65° C. for 1 h. The reaction mixture wasthen filtered through a pad of celite and concentrated to obtain an offwhite solid. Column chromatography (silica, 0-5% MeOH/CH₂Cl₂) provided135 mg (75%) of product as a white solid. TLC (silica, 10% MeOH/CH₂Cl₂):R_(f)=0.50. MS (electrospray): exact mass calculated for C₁₉H₂₈N₄O₂,344.22; m/z found, 345.2 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz): 8.53 (s, 1H),8.30 (br s, 1H), 6.67 (dd, J=1.17 Hz, 0.78 Hz, 1H), 6.34 (d, J=0.78 Hz,1H), 4.33-4.16 (m, 2H), 3.05 (s, 6H), 2.97-2.80 (m, 3H), 1.99 (d,J=12.72 Hz, 2H), 1.69-1.53 (m, 2H), 1.46 (s, 9H).

[0348] E.Dimethyl-(3-piperidin-4-yl-1H-pyrrolo[3,2-c]pyridin-6-yl)-amine.

[0349] The4-(6-dimethylamino-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylicacid tert-butyl ester (135 mg, 0.39 mmol) was set stirring in 1:1TFA/CH₂Cl₂. After 45 min the mixture was evaporated. The residue wasdissolved in MeOH (10 mL) and neutralized with DOWEX 550A OH anionexchange resin to pH 8. The resin was then filtered off and MeOH wasremoved under reduced pressure to give 96 mg (100%) of a yellow solid.MS (electrospray): exact mass calculated for C₁₄H₂₀N₄, 244.17; m/zfound, 245.2 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz): 9.23 (br s, 1H), 8.54 (s,1H), 6.67 (s, 1H), 6.31 (d, J=0.98 Hz, 1H), 3.15 (d, J=2.13 Hz, 2H),3.02 (s, 6H), 2.91-2.81 (m, 1H), 2.81-2.72 (m, 2H), 2.01 (d, J=12.52 Hz,2H), 1.69-1.52 (m, 2H).

[0350] F. 1-[4-(6-Dimethylamino-1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolc]pyridin-1-yl]-propan-2-ol.

[0351] Dimethyl-(3-piperidin-4-yl-1H-pyrrolo[3,2-c]pyridin-6-yl)-amine(96 mg, 0.53 mmol) and5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(319 mg, 0.80 mmol) were set stirring in ^(i)PrOH (10 mL) at 80° C.After 16 h the mixture was cooled and concentrated. The residue waspurified by column chromatography (silica, 0-10% (2 N NH₃ inMeOH)/CH₂Cl₂ to obtain 61 mg (18%) of a white solid. TLC (silica, 10%MeOH/CH₂Cl₂): R_(f)=0.12. MS (electrospray): exact mass calculated forC₃₁H₃₈F₇N₇O₃S, 645.27; m/z found, 646.3 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz):8.53 (s, 1H), 7.93 (br s, 1H), 7.71 (d, J=8.22 Hz, 2H), 7.64 (d, J=8.22,2H), 6.67 (br s, 1H), 6.33 (d, J=0.98 Hz, 1H), 4.54 (dd, J=14.28 Hz,9.59 Hz, 2H), 4.22-4.10 (m, 2H), 4.04-3.97 (m, 1H), 3.74-3.57 (m, 2H),3.13-3.06 (m, 1H), 3.05 (s, 6H), 3.03-2.87 (m, 3H), 2.85 (s, 3H),2.82-2.71 (m, 1H), 2.50-2.37 (m, 3H), 2.20-2.11 (m, 1H), 2.06-1.97 (m,2H), 1.82-1.61 (m, 2H).

Example 9

[0352]

[0353]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-morpholin-4-yl-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

[0354] A. 4-(5-Methyl-4-nitro-1-oxy-pyridin-2-yl)-morpholine.

[0355] A solution of 2-bromo-5-methyl-4-nitro-pyridine 1-oxide (500 mg,2.14 mmol) in morpholine (15 mL) was heated at 70° C. for 16 h. Thesolvent was evaporated under reduced pressure. The residue was purifiedby column chromatography (silica, 30-80% EtOAc/hexanes) to obtain 480 mg(94%) of the desired product. TLC (silica, 50% EtOAc/hexanes):R_(f)=0.10. MS (electrospray): exact mass calculated for C₁₀H₁₃N₃O₄,239.09; m/z found, 240.1 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz): 8.09 (s, 1H),7.55 (s, 1H), 3.90 (t, J=4.50 Hz, 4H), 3.36 (t, J=4.70 Hz, 4H), 2.50 (s,3H).

[0356] B. 6-Morpholin-4-yl-1H-pyrrolo[3,2-c]pyridine.

[0357] A solution of 4-(5-methyl-4-nitro-1-oxy-pyridin-2-yl)-morpholine(480 mg, 2 mmol) in DMF (5 mL) was treated with DMF-dimethylacetal (533μL, 4 mmol) and the reaction mixture was stirred at 100° C. for 4 h. Allvolatiles were removed under reduced pressure. The red powder wastreated with ammonium formate (1.26 g, 20 mmol) and 10% Pd—C (212 mg).The reaction mixture was stirred at 65° C. for 30 min. The reactionmixture was then filtered through a pad of celite and concentrated toobtain a yellow solid. Column chromatography (silica, 5% MeOH/CH₂Cl₂)provided 197 mg (49% for two steps) of a yellow solid. TLC (silica, 10%MeOH/CH₂Cl₂): R_(f)=0.55. MS (electrospray): exact mass calculated forC₁H₁₃N₃O, 203.11; m/z found, 204.1 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz) 8.68(br s, 1H), 8.59 (s, 1H), 7.04 (dd, J=2.15 Hz, 1.17 Hz, 1H), 6.51 (s,1H), 6.49-6.47 (m, 1H), 3.86 (t, J=4.70 Hz, 4H), 3.40 (t, J=4.70 Hz,4H).

[0358] C.4-(6-Morpholin-4-yl-1H-pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicAcid Tert-butyl Ester.

[0359] 6-Morpholin-4-yl-1H-pyrrolo[3,2-c]pyridine (197 mg, 0.97 mmol),4-oxo-piperidine-1-carboxylic acid tert-butyl ester (387 mg, 1.94 mmol)and potassium hydroxide (218 mg, 3.88 mmol) were added in MeOH (10 mL)and heated to reflux for 16 h. The reaction mixture was then cooled toroom temperature and poured into ice water (50 mL). The mixture wasextracted with 10% MeOH/CH₂Cl₂ (5×20 mL). The organic extracts was driedover Na₂SO₄ and concentrated. The residue was purified by columnchromatography (silica, 0-5% MeOH/CH₂Cl₂) to obtain 337 mg (91%) of thedesired product. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.50. MS(electrospray): exact mass calculated for C₂₁H₂₈N₄O₃, 384.22; m/z found,749.3 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz): 9.24 (br s, 1H), 8.77 (s, 1H),6.95 (d, J=2.15 Hz, 1H), 6.45 (s, 1H), 6.09 (br s, 1H), 4.09-4.04 (m,2H), 3.66 (t, J=6.06 Hz, 4H), 3.60 (t, J=5.28 Hz, 2H), 3.25 (t, J=5.09Hz, 4H), 2.38 (d, J=6.26 Hz, 2H), 1.44 (s, 9H).

[0360] D.4-(6-Morpholin-4-yl-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylicAcid Tert-butyl Ester.

[0361]4-(6-Morpholin-4-yl-1H-pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (337 mg, 0.9 mmol) in MeOH (20 mL) was treatedwith ammonium formate (568 mg, 9.0 mmol) and 10% Pd—C (95 mg). Thereaction mixture was stirred at 65° C. for 1 h. The reaction mixture wasthen filtered through a pad of celite and concentrated to obtain anoff-white solid. Column chromatography (silica, 0-5% MeOH/CH₂Cl₂)provided 340 mg (98%) of a white solid. TLC (silica, 5% MeOH/CH₂Cl₂):R_(f)=0.40. MS (electrospray): exact mass calculated for C₂₁H₃₀N₄O₃,386.23; m/z found, 387.3 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz) 9.14 (br s,1H), 8.55 (s, 1H), 6.74 (d, J=1.96 Hz, 1H), 6.45 (s, 1H), 4.27-4.08 (m,2H), 3.80 (t, J=4.50 Hz, 4H), 3.34 (t, J=4.89 Hz, 4H), 2.96-2.77 (m,3H), 1.97 (d, J=12.91 Hz, 2H), 1.67-1.52 (m, 2H), 1.44 (s, 9H).

[0362] E. 6-Morpholin-4-yl-3-piperidin-4-yl-1H-pyrrolo[3,2-c]pyridine.

[0363]4-(6-Morpholin-4-yl-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylicacid tert-butyl ester (380 mg, 0.98 mmol) was set stirring in 1:1TFA/CH₂Cl₂. After 45 min the mixture was evaporated. The residue wasdissolved in MeOH (20 mL) and neutralized with DOWEX 550A OH anionexchange resin to pH 8. The resin was then filtered off and MeOH wasremoved under reduced pressure to give 281 mg (100%) of a yellow solid.MS (electrospray): exact mass calculated for C₁₆H₂₂N₄O, 286.18; m/zfound, 287.1 [M⁺+H].

[0364] F.1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-morpholin-4-yl-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

[0365] 6-Morpholin-4-yl-3-piperidin-4-yl-1H-pyrrolo[3,2-c]pyridine (281mg, 0.98 mmol) and5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(591 mg, 1.47 mmol) were set stirring in ^(i)PrOH (10 mL) at 80° C.After 16 h the mixture was cooled and concentrated. The residue waspurified by column chromatography (silica, 0-10% (2 N NH₃ inMeOH)/CH₂Cl₂) to obtain 468 mg (69%) of a white solid. TLC (silica, 10%(2 N NH₃ in MeOH)/CH₂Cl₂): R_(f)=0.62. MS (electrospray): exact masscalculated for C₃₃H₄₀F₃N₇O₄S, 687.28; m/z found, 688.3 [M⁺+H]. ¹H NMR(CDCl₃, 400 MHz): 8.56 (s, 1H), 8.40 (br s, 1H), 7.69 (d, J=8.41 Hz,2H), 7.63 (d, J=8.41, 2H), 6.73 (br s, 1H), 6.46 (s, 1H), 4.51 (dd,J=14.28 Hz, 8.80 Hz, 2H), 4.21-4.10 (m, 2H), 4.03-3.95 (m, 1H), 3.82 (t,J=4.11 Hz, 4H), 3.71-3.54 (m, 2H), 3.36 (t, J=4.89 Hz, 4H), 3.10-2.97(m, 2H), 2.93-2.86 (m, 2H), 2.84 (s, 3H), 2.82-2.72 (m, 1H), 2.50-2.37(m, 3H), 2.20-2.10 (m, 1H), 2.04-1.95 (m, 2H), 1.80-1.60 (m, 2H).

Example 10

[0366]

[0367]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-morpholin-4-yl-5-oxy-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

[0368] A. 6-Morpholin-4-yl-1H-pyrrolo[3,2-c]pyridine 5-oxide.

[0369] A solution of 4-(5-methyl-4-nitro-1-oxy-pyridin-2-yl)-morpholine(480 mg, 2 mmol) in DMF (5 mL) was treated with DMF-dimethylacetal (533μL, 4 mmol) and the reaction mixture was stirred at 100° C. for 4 h. Allvolatiles were removed under reduced pressure. The red powder wastreated with ammonium formate (1.26 g, 20 mmol) and 10% Pd—C (212 mg).The reaction mixture was stirred at 65° C. for 30 min. The reactionmixture was then filtered through a pad of celite and concentrated toobtain a yellow solid. Column chromatography (silica, 5% MeOH/CH₂Cl₂)provided 130 mg (30% for two steps) of a yellow solid. TLC (silica, 10%MeOH/CH₂Cl₂): R_(f)=0.28. MS (electrospray): exact mass calculated forC₁₁H₁₃N₃O₂, 219.10; m/z found, 220.1 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz):8.42 (br s, 1H), 7.25 (s, 1H), 7.14 (s, 1H), 6.82 (s, 1H), 6.35 (s, 1H),3.79 (t, J=4.70 Hz, 4H), 3.18 (t, J=4.70 Hz, 4H).

[0370] B.4-(6-Morpholin-4-yl-5-oxy-1H-pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicAcid Tert-butyl Ester.

[0371] 6-Morpholin-4-yl-1H-pyrrolo[3,2-c]pyridine 5-oxide (130 mg, 0.59mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (237 mg, 1.19mmol) and potassium hydroxide (133 mg, 2.37 mmol) were added in MeOH (8mL) and heated to reflux for 16 h. The reaction mixture was then cooledto room temperature and poured into ice water (30 mL). The mixture wasextracted with 10% MeOH/CH₂Cl₂ (5×10 mL). The organic extracts was driedover Na₂SO₄ and concentrated. The residue was purified by columnchromatography (silica, 0-5% MeOH/CH₂Cl₂) to obtain 140 mg (59%) of thedesired product. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.55. MS(electrospray): exact mass calculated for C₂₁H₂₈N₄O₄, 400.21; m/z found,401.2 (M⁺+H).

[0372] C.4-(6-Morpholin-4-yl-5-oxy-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylicAcid Tert-butyl Ester.

[0373]4-(6-Morpholin-4-yl-5-oxy-1H-pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (140 mg, 0.35 mmol) in EtOH (20 mL) containingPtO₂ (50 mg) was placed on a Parr hydrogenator at 60 psi H₂. After 18 hmixture was filtered through celite and evaporated to give a whitesolid. Column chromatography (silica, 0-5% (2 N NH₃ in MeOH)/CH₂Cl₂)provided 56 mg (40%) of a white solid. TLC (silica, 5% MeOH/CH₂Cl₂):R_(f)=0.13. MS (electrospray): exact mass calculated for C₂₁H₃₀N₄O₄,402.23; m/z found, 403.2 (M⁺+H). ¹H NMR (CDCl₃, 400 MHz): 11.63 (br s,1H), 8.58 (s, 1H), 6.97 (br s, 1H), 6.69 (s, 1H), 4.26-4.08 (m, 2H),3.73 (t, J=4.30 Hz, 4H), 3.17 (t, J=4.50 Hz, 4H), 2.92-2.74 (m, 3H),1.91 (d, J=11.93 Hz, 2H), 1.62-1.50 (m, 2H), 1.43 (s, 9H).

[0374] D. 6-Morpholin-4-yl-3-piperidin-4-yl-1H-pyrrolo[3,2-c]pyridine5-oxide.

[0375]4-(6-Morpholin-4-yl-5-oxy-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylicacid tert-butyl ester (56 mg, 0.14 mmol) was set stirring in 1:1TFA/CH₂Cl₂. After 45 min the mixture was evaporated. The residue wasdissolved in MeOH (10 mL) and neutralized with DOWEX 550A OH anionexchange resin to pH 8. The resin was then filtered off and MeOH wasremoved under reduced pressure to give 42 mg (100%) of a yellow solid.MS (electrospray): exact mass calculated for C₁₆H₂₂N₄O₂, 302.17; m/zfound, 303.1 [M⁺+H].

[0376] E.1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-morpholin-4-yl-5-oxy-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

[0377] 6-Morpholin-4-yl-3-piperidin-4-yl-1H-pyrrolo[3,2-c]pyridine5-oxide (42 mg, 0.14 mmol) and5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(84 mg, 0.21 mmol) were set stirring in ^(i)PrOH (5 mL) at 80° C. After6 h the mixture was cooled and concentrated. The residue was purified bycolumn chromatography (silica, 0-10% (2 N NH₃ in MeOH)/CH₂Cl₂) to obtain5.1 mg (5%) of a white solid. TLC (silica, 10% (2 N NH₃ inMeOH)/CH₂Cl₂): R_(f)=0.54. MS (electrospray): exact mass calculated forC₃₃H₄₀F₃N₇O₅S, 703.28; m/z found, 704.3 [M⁺+H]. ¹H NMR (CDCl₃, 400 MHz):8.60 (s, 1H), 7.71 (d, J=8.41 Hz, 2H), 7.66 (d, J=8.41, 2H), 7.27 (s,1H), 6.95 (s, 1H), 6.70 (s, 1H), 4.55 (dd, J=14.48 Hz, 3.13 Hz, 2H),4.23-4.11 (m, 2H), 4.05-3.97 (m, 1H), 3.84 (t, J=4.30 Hz, 4H), 3.72-3.60(m, 2H), 3.23 (t, J=4.30 Hz, 4H), 3.12-2.98 (m, 2H), 2.97-2.89 (m, 2H),2.88 (s, 3H), 2.73-2.63 (m, 1H), 2.51-2.36 (m, 3H), 2.17-2.08 (m, 1H),1.99-1.90 (m, 2H), 1.78-1.58 (m, 2H).

Example 11

[0378]

[0379]6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b]thiophene-2-carboxylicAcid (2-hydroxy-ethyl)-amide.

[0380] A. 1-[4-(2,4-Difluoro-benzoyl)-piperidin-1-yl]-ethanone.

[0381] A stirred solution of 10 g (58.5 mmol) of1-acetylpiperidine-4-carboxylic acid in anhydrous dichloroethane (35 mL)was treated with 5.1 mL (70.2 mmol) of thionyl chloride in 7 mL ofdichloroethane and then heated to 60° C. for 30 min. Another flaskcontaining a suspension of 8.02 mL (81.8 mmol) of 1,3-difluorobenzeneand 17.9 g (134 mmol) of aluminum chloride in 55 mL of dichloroethanewas prepared, to this was added the previously prepared acid chloridesuspension in portions. The resulting suspension was refluxed for 4 h,cooled and then poured over ice and HCl. The acidic solution wasextracted with CH₂Cl₂ (3×300 mL) and the combined organic extracts werewashed with brine, dried over Na₂SO₄, and concentrated. The crudeproduct was recrystallized from hexanes to afford 9.5 g (61%) of thedesired product as a white solid. MS (electrospray): exact masscalculated for C₁₄H₁₅F₂NO₂, 267.11; m/z found, 268.1 [M+H]⁺, ¹H NMR(CDCl₃, 400 MHz): 7.87 (dt, J=8.41, 6.65 Hz 1H), 6.98 (m, 1H), 6.88(ddd, J=10.96, 8.61, 2.35 Hz, 1H), 4.55 (m, 1H), 3.87 (m, 1H), 3.32(dtt, J=10.76, 3.91, 1.37 Hz, 1H), 3.19 (ddd, J=13.89, 11.93, 2.93 Hz,1H), 2.79 (ddd, J=13.89, 12.24, 2.93 Hz, 1H), 2.10 (s, 3H), 1.95 (br d,J=12.91 Hz, 2H), 1.72 (br m, 1H), 1.56 (br m, 1H).

[0382] B.3-(1-Acetyl-piperidin-4-yl)-6-fluoro-benzo[b]thiophene-2-carboxylic acidmethyl ester.

[0383] To a stirred solution of 33.6 g (0.126 mol) of1-[4-(2,4-difluoro-benzoyl)-piperidin-1-yl]-ethanone and 13 mL (145 mol)of methyl thioglycolate in 320 mL dry THF was added 5.8 g (145 mol) of60% sodium hydride in mineral oil in portions. The reaction mixture washeated to reflux overnight, allowed to cool to room temperature and thesolvent removed under reduced pressure. The residue was then partitionedbetween 300 mL of CH₂Cl₂ and 200 mL of water. The aqueous layer wasfurther extracted with CH₂Cl₂ (2×500 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄, and concentrated to give aresidue which was then triturated with hexanes/EtOAc to give 27.5 g(65%) of the desired product as a white solid. MS (electrospray): exactmass calculated for C₁₇H₁₈FNO₃S, 335.1; m/z found, 336.1 [M+H]⁺. ¹H NMR(DMSO-d₆, 400 MHz, a mixture of amide rotamers): 7.12 (m, 2H), 6.92 (dt,J=8.41, 1.77 Hz, 1H), 4.43 (d, J=3.79 Hz, 1H), 4.43-4.36 (m, 1H), 3.82(bt, J=14.65 Hz, 1H), 3.57 (s, 3H), 2.92-2.79 (m, 1H), 2.38-2.34 (m,1H), 1.94 (s, 1.5H), 1.93 (s, 1.5H), 1.86-1.72 (m, 1H), 1.47-1.38 (m,1H), 1.38-1.27 (m, 0.5H), 1.27-1.16 (m, 1H), 1.15-1.03 (m, 0.5H).

[0384] C. 6-Fluoro-3-piperidin-4-yl-benzo[b]thiophene-2-carboxylic AcidMethyl Ester Hydrochloride salt.

[0385] A solution of 24.4 g (66.8 mmol) of3-(1-acetyl-piperidin-4-yl)-6-fluoro-benzo[b]thiophene-2-carboxylic acidmethyl ester in 400 mL of MeOH and 50 mL of concentrated HCl was heateda reflux for 2 days. When the solution was allowed to cool to roomtemperature the white precipitate was filtered, washed with methanol anddried to give 17.9 g (74%) of product as a white powder. MS(electrospray): exact mass calculated for C₁₅H₁₆FNO₂S, 293.09; m/zfound, 294.1 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz): 9.38 (br s, 1H), 9.02(br s, 1H), 8.60 (dd, J=9.19, 5.09 Hz, 1H), 7.98 (dd, J=9.00, 2.54 Hz,1H), 7.36 (dt, J=9.00, 2.54 Hz, 1H), 4.37 (br t, J=12.72 Hz, 1H), 3.87(s, 3H), 3.40 (br d, J=11.93 Hz, 2H), 3.02 (q, J=11.35 Hz, 2H), 2.61(dq, J=13.30, 3.72 Hz, 2H), 1.77 (br d, J=12.91 Hz, 2H).

[0386] D.3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-1-ol.

[0387] Cs₂CO₃ (33.74 g, 103.5 mmol) was added to a solution of5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(29.8 g, 86.3 mmol) in anhydrous DMF (70 mL) and stirred for 25 min.3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) was added and stirredunder N₂ at room temperature for 18 h. Water (500 mL) was added to thereaction and stirred for 5 min. The precipitated material was filteredout and washed with water (4×100 mL) and dried. The crude material (31.0g) was taken up in anhydrous DMF (65 mL) and Cs₂CO₃ (33.74 g, 103.5mmol) was added, and stirred for 10 min. Then 3-bromo-1-propanol (8.6mL, 13.2 g, 94.9 mmol) and MeOH (6.0 mL, 4.75 g, 148 mmol) were addedand stirring continued under N₂ at rt for 15 h. Water (500 mL) was addedto the reaction and stirred for 10 min. The precipitated material wasfiltered and washed with water (3×100 mL). The filter cake was dissolvedin CH₂Cl₂ (200 mL) and washed with brine (50 mL), dried (Na₂SO₄), andconcentrated. The solid was triturated with Et₂O (200 mL), filtered,then washed with Et₂O, and dried to furnish 16.0 g of the desiredcompound. The mother liquor was chromatographed (silica, 0-10%acetone/EtOAc) to obtain an additional 3.0 g of the title compound. Thecombined yield was 54.6%. MS (electrospray): exact mass calculated forC₁₇H₂OF₃N₃O₃S, 403.12; m/z found, 404.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.71 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 4.55 (s, 2H), 4.23 (t,J=6.5 Hz, 2H), 3.70-3.63 (m, 4H), 2.90 (s, 3H), 2.90 (t, J=5.1 Hz, 2H),2.62 (t, J=5.9 Hz, 1H), 2.06 (q, J=6.1 Hz, 2H).

[0388] E.3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde.

[0389] Dess-Martin periodinane (3.45 g, 8.2 mmol) was added to asolution of3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-1-ol(3.0 g, 7.4 mmol) in CH₂Cl₂ (20 mL) at 0° C. under N₂. After 15 min, thereaction was allowed to warm to room temperature and stirred for another1.5 h. The reaction was diluted with Et₂O (60 mL) and 20% aq. NaHCO₃ (35mL) was added slowly (caution! rapid gas evolution). Then Na₂S₂O₃ wasadded and stirred at room temperature for 30 min. The layers wereseparated and the aqueous portion was extracted with Et₂O (2×30 mL). Thecombined organic extracts were washed with brine, dried (Na₂SO₄) andconcentrated. MPLC (silica, 1-10% MeOH/CH₂Cl₂) afforded 2.53 g of thedesired aldehyde in 85% yield. MS (electrospray): exact mass calculatedfor C₁₇H₁₈F₃N₃O₃S, 401.11; m/z found, 402.1 [M+H]. ¹H NMR (400 MHz,CDCl₃): 9.82 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H),4.68 (s, 2H), 4.25 (t, J=6.1 Hz, 2H), 3.63 (t, J=5.8 Hz, 4H), 3.14 (t,J=6.1 Hz, 2H), 2.92 (t, J=5.8 Hz, 2H), 2.81 (s, 3H).

[0390] F.6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b]thiophene-2-carboxylicAcid Methyl Ester.

[0391] To a stirred solution of 410 mg (1.25 mmol) of6-fluoro-3-piperidin-4-yl-benzo[b]thiophene-2-carboxylic acid methylester hydrochloride salt in 10 mL of dichloromethane and 0.18 mL (1.25mmol) of triethylamine was added 500 mg of3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde(1.25 mmol) and 2 g of NaHCO₃. The mixture was stirred for 4 h beforethe portion wise addition of 792 mg (3.73 mmol) sodiumtriacetoxyborohydride. The reaction was stirred at room temperature for3 h before quenching with 20 mL of water. The aqueous phase wasextracted with CH₂Cl₂ (3×50 mL). The combined organic layers were thenwashed with brine, dried over Na₂SO₄, and concentrated. The crudeproduct was purified by column chromatography (silica, 0-5% MeOH/CH₂Cl₂)to afford 650 mg (77%) of a white solid. MS (electrospray): exact masscalculated for C₃₂H₃₄F₄N₄O₄S₂: 678.20; m/z found, 679.2 [M+H]⁺. ¹H NMR(CDCl₃, 400 MHz): 7.74 and 7.66 (A and B of AB quartet, J=8.22 Hz, 4H),7.50 (dd, J=8.41, 2.54 Hz 1H), 7.14 (t, J=8.22 Hz, 1H), 4.56 (s, 2H),4.17 (m, 3H), 3.91 (s, 3H), 3.70 (t, J=5.67 Hz, 2H), 3.03 (br m, 2H),3.00 (t, J=5.67 Hz, 2H), 2.90 (s, 3H), 2.40 (br m, 4H), 2.13 (br m, 4H),1.76 (br d, J=11.15 Hz, 4H).

[0392] G.6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b]thiophene-2-carboxylicAcid.

[0393] To a stirred solution of 635 mg (0.94 mmol) of6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylicacid methyl ester in 10 mL of THF was treated a solution of 53 mg (0.94mmol) of KOH in 0.5 mL of water. This was stirred overnight, after thehydrolysis was deemed complete 1 mL of 1 N HCl solution was added. Thiswas then extracted with EtOAc (3×30 mL). The combined organic layerswere then washed with brine, dried over Na₂SO₄, and concentrated toyield 622 mg (100%) of a white solid. MS (electrospray): exact masscalculated for C₃₁H₃₂F₄N₄O₄S₂: 664.18; m/z found, 665.2 [M+H]⁺. ¹H NMR(DMSO-d₆, 400 MHz): 8.12 (dd, J=8.81, 5.28 Hz, 1H), 7.83 and 7.76 (A andB of AB quartet, J=8.41 Hz, 4H), 7.17 (br t, J=8.61 Hz, 1H), 4.47 (s,2H), 4.29 (brs, 1H), 4.16 (t, J=7.04 Hz, 2H), 3.53 (t, J=5.67 Hz, 2H),3.28 (br m, 4H), 3.00 (s, 3H), 2.96 (m, 2H), 2.73 (br s, 2H), 2.52 (brm, 2H), 2.13 (br m, 2H), 1.76 (br m, 2H).

[0394] H.6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b]thiophene-2-carboxylicAcid (2-hydroxy-ethyl)-amide.

[0395] A stirred solution of 20 mg (0.03 mmol) of6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylicacid in 0.3 mL of dry DMF was treated with 14 mg (0.036 mmol) of HBTUand 8 μL (0.045 mmol) of DIEA. The solution was stirred for 5 min beforethe addition of 0.01 mL (0.15 mmol) of ethanol amine. The reaction wasstirred at room temperature for 30 min then partitioned between EtOAc(30 mL) and saturated NaHCO₃ (20 mL). The aqueous layer was furtherextracted with EtOAc (2×20 mL). The combined organic layers were thenwashed with brine, dried over Na₂SO₄, and concentrated. Purification bycolumn chromatography (silica, 5-10% of 2 N NH₃ in MeOH/CH₂Cl₂) yielded16 mg (76%) of a white solid. MS (electrospray): exact mass calculatedfor C₃₃H₃₇F₄N₅O₄S₂: 707.22; m/z found, 708.2 [M+H]⁺. ¹H NMR (CDCl₃, 400MHz): 7.97 (br s, 1H), 7.73 and 7.66 (A and B of AB quartet, J=8.41 Hz,4H), 7.49 (dd, J=8.41, 2.35 Hz, 1H), 7.15 (dt, J=8.61, 2.54 Hz, 1H),6.41 (t, J=5.67 Hz, 1H), 4.56 (s, 2H), 4.16 (t, J=7.04 Hz, 2H), 3.84(dd, J=5.28, 4.70 Hz, 2H), 3.70 (t, J=5.67 Hz, 2H), 3.62 (m, 2H), 3.58(br s, 1H), 3.05 (br m, 2H), 2.97 (t, J=5.67 Hz, 2H), 2.91 (s, 3H), 2.40(br m, 4H), 2.13 (br m, 4H), 1.84 (br d, J=12.32 Hz, 2H).

Example 12

[0396]

[0397]6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b]thiophene-2-carboxylicAcid (2-amino-ethyl)-amide.

[0398] A stirred solution of 300 mg (0.43 mmol)6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylicacid in 5 mL of dry DMF was treated with 812 mg (2.14 mmol) of HBTU and0.75 mL (4.28 mmol) of DIEA. The solution was stirred for 5 min beforethe addition of 0.28 mL (4.28 mmol) of ethylenediamine. The reaction wasstirred at room temperature for 30 min then partitioned between EtOAc(30 mL) and saturated sodium bicarbonate (20 mL). The aqueous layer wasfurther extracted with EtOAc (2×20 mL). The combined organic layers werethen washed with brine, dried over Na₂SO₄, and concentrated.Purification by column chromatography (silica, 5-10% of (2 N NH₃ inMeOH)/CH₂Cl₂) afforded 200 mg (66%) of a clear oil. MS (electrospray):exact mass calculated for C₃₃H₃₈F₄N₆O₃S₂: 706.24; m/z found, 707.2[M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): 8.14 (m, 1H), 7.84 and 7.72 (A and B ofAB quartet, J=8.41 Hz, 4H), 7.68 (m, 1H), 7.21 (dt, J=8.81, 2.74 Hz,1H), 4.54 (s, 2H), 4.27 (t, J=6.26 Hz, 2H), 4.00-3.90 (m, 2H), 3.76-3.61(m, 8H), 3.28-3.23 (br m, 1H), 3.19-3.09 (br m, 3H), 2.98 (s, 3H),2.97-2.93 (m, 2H), 2.67 (br m, 2H), 2.52-2.37 (m, 3H), 2.02 (br d,J=13.89 Hz, 2H).

Example 13

[0399]

[0400]6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b]thiophene-2-carboxylicAcid (2-morpholin-4-yl-ethyl)-amide.

[0401] A stirred solution of 20 mg (0.03 mmol) of6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylicacid in 0.3 mL of dry DMF was treated with 14 mg (0.036 mmol) of HBTUand 8 μL (0.045 mmol) of DIEA. The solution was stirred for 5 min beforethe addition of 20 μL (0.15 mmol) of 4-(2-aminoethyl)morpholine. Thereaction was stirred at room temperature for 30 min then partitionedbetween EtOAc (30 mL) and saturated NaHCO₃ (20 mL). The aqueous layerwas further extracted with EtOAc (2×20 mL). The combined organic layerswere then washed with brine, dried over Na₂SO₄, and concentrated.Purification by column chromatography (silica, 5-10% of (2 N NH₃ inMeOH)/CH₂Cl₂) afforded 15 mg (65%) of a white solid. MS (electrospray),exact mass calculated for C₃₇H₄₄F₄N₆O₄S₂: 776.28; m/z found, 777.3[M+H]⁺. ¹H NMR (CDCl₃, 400 MHz): 8.07 (br s, 1H), 7.73 and 7.66 (A and Bof AB quartet, J=8.41 Hz, 4H), 7.50 (dd, J=8.41, 2.35 Hz, 1H), 7.14 (dt,J=8.61, 2.54 Hz, 1H), 6.64 (t, J=4.70 Hz, 1H), 4.56 (s, 2H), 4.16 (t,J=6.85 Hz, 2H), 3.80-3.67 (m, 7H), 3.53 (q, J=5.48 Hz, 2H), 3.03 (br m,2H), 2.98 (t, J=5.67 Hz, 2H), 2.90 (s, 3H), 2.60 (t, J=5.87 Hz, 2H),2.38 (br m, 4H), 2.12 (br m, 4H), 1.86-1.73 (br m, 3H).

Example 14

[0402]

[0403]1-[1-{2-Hydroxy-3-[4-(1H-indol-3-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.

Example 15

[0404]

[0405]1-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.

Example 16

[0406]

[0407]1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-chloro-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol.

Example 17

[0408]

[0409]1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-chloro-2-methyl-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol.

Example 18

[0410]

[0411]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-methyl-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol.

Example 19

[0412]

[0413]3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-indole-5-carbonitrile.

Example 20

[0414]

[0415]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-methoxy-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol.

Example 21

[0416]

[0417]3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-indole-5-carboxylicacid ethyl ester.

Example 22

[0418]

[0419]1-[4-(6-Chloro-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.

Example 23

[0420]

[0421]1-[1-(3-{4-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-2-hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.

Example 24

[0422]

[0423]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-b]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

Example 25

[0424]

[0425]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

Example 26

[0426]

[0427]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-oxy-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

Example 27

[0428]

[0429]1-[4-(5-Dimethylamino-1H-pyrrolo[3,2-b]pyridin-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.

Example 28

[0430]

[0431]1-[4-(5-Dimethylamino-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.

Example 29

[0432]

[0433]3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile.

Example 30

[0434]

[0435]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-{4-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-propan-2-ol.

Example 31

[0436]

[0437]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(7-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol.

Example 32

[0438]

[0439]1-[4-(6-Fluoro-2-hydroxymethyl-benzo[b]thiophen-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.

Example 33

[0440]

[0441]6-Fluoro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carbaldehyde.

Example 34

[0442]

[0443]6-Fluoro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylicacid methyl ester.

Example 35

[0444]

[0445]6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b]thiophene-2-carboxylicacid amide.

Example 36

[0446]

[0447]6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b]thiophene-2-carboxylicacid ethylamide.

Example 37

[0448] Cathepsin S Inhibition Assay.

[0449] Recombinant human cathepsin S (CatS) was expressed in thebaculovirus system and purified in one step with a thiopropyl-sepharosecolumn. 10-L yielded ˜700 mg of CatS and N-terminal sequencing confirmedidentity. The assay is run in 100 mM sodium acetate pH 5.0 containing 1mM DTT and 100 mM NaCl. The substrate for the assay is

(Aedens)EKARVLAEAA(Dabcyl)K−amide

[0450] The K_(m) for the substrate is around 5 μM but the presence ofsubstrate inhibition makes kinetic analysis difficult. With 20 μMsubstrate the assay rate is linear over the range of 1-8 ng CatS in 100μl reaction. Using 2 ng/well of CatS, the production of product islinear and yields ˜7-fold signal after 20 min with only 20% loss ofsubstrate. Primary assays are run by quenching the reaction after 20 minwith 0.1% SDS and then measuring the fluorescence. For other assays,measurements are taken every min for 20 min. The rate is calculated fromthe slope of the increase and the percent inhibition is calculated fromthis (See Tables 1, 2 and 3 below). TABLE 1 EXAMPLE IC₅₀ (μM)  1 0.07  20.03  3 0.05  4 0.09  5 0.03  6 0.03  7 0.05  8 0.03  9 0.02 10 0.02 110.02 12 0.05 13 0.05

[0451] TABLE 2 EXAMPLE IC₅₀ (μM) 14 0.07 15 0.04 16 0.06 17 0.03 18 0.0619 0.02 20 0.02 21 0.04 22 0.03 23 0.08 24 0.13 25 0.05 26 0.09 27 0.1028 0.07 29 0.08 30 0.02 31 0.07 32 0.14 33 0.08 34 0.13 35 0.03 36 0.04

Example 101

[0452]1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(1H-indol-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone

Example 102

[0453]1-[1-{3-[4-(5-Chloro-1H-indol-3-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Example 103

[0454]1-{3-[4-(5-Chloro-1H-indol-3-yl)-piperidin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

Example 104

[0455]3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-indole-5-carbonitrile

Example 105

[0456]1-[4-(6-Chloro-1-methyl-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol

Example 106

[0457]1-[4-(6-Chloro-1-methanesulfonyl-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol

Example 107

[0458]1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(7-chloro-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol

Example 108

[0459]3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1H-indole-5-carbonitrile

Example 109

[0460]1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-{4-[6-chloro-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-propan-2-ol

Example 110

[0461]1-[3-(4-Bromo-phenyl)-1-(3-{4-[6-chloro-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-2-hydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Example 111

[0462]1-[1-{2-Hydroxy-3-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Example 112

[0463]1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol

Example 113

[0464]1-(3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone

Example 114

[0465]1-[1-(2-Hydroxy-3-{4-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Example 115

[0466]5-Methanesulfonyl-1-{3-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

Example 116

[0467]5-Methanesulfonyl-1-{3-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

Example 117

[0468]1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-{4-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-propan-2-ol

Example 118

[0469]1-[3-(4-Bromo-phenyl)-1-(2-hydroxy-3-{4-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Example 119

[0470]6-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid methyl ester

Example 120

[0471]1-[4-(6-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol

Example 121

[0472]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(7-oxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol

Example 122

[0473]1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol

Example 123

[0474]1-[1-{2-Hydroxy-3-[4-(1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Example 124

[0475]1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol

Example 125

[0476]1-(3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone

Example 126

[0477]3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-oxy-pyrrolo[3,2-c]pyridine-1-carboxylicacid methyl ester

Example 128

[0478]3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-fluoro-benzofuran-2-carboxylicacid methyl ester

Example 129

[0479]3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-fluoro-benzo[b]thiophene-2-carboxylicacid methyl ester

Example 130

[0480]1-[4-(6-Fluoro-benzo[b]thiophen-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol

Example 131

[0481]1-[1-{3-[4-(6-Fluoro-benzofuran-3-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Example 132

[0482]6-Fluoro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylicacid

Example 133

[0483]6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylicacid dimethylamide

Example 134

[0484]3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-fluoro-benzo[b]thiophene-2-carbonitrile

Example 135

[0485]6-Fluoro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carbonitrileTABLE 3 EXAMPLE IC₅₀ (μM) 101 0.25 102 0.11 103 0.16 104 0.14 105 0.63106 0.20 107 0.04 108 0.04 109 0.08 110 0.14 111 0.17 112 0.13 113 0.20114 0.11 115 0.59 116 0.25 117 0.10 118 0.26 119 0.69 120 0.25 121 0.31122 0.19 123 0.15 124 0.13 125 0.21 126 0.25 127 0.40 128 0.23 130 0.19131 0.37 132 0.09 133 0.38 134 0.38 135 0.21

[0486] F. Other Embodiments

[0487] The features and advantages of the invention are apparent to oneof ordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. These other embodimentsare also within the scope of the invention.

What is claimed is:
 1. A compound of formula (I):

wherein: the dashed line adjacent C—R⁶ is absent or an sp² bond; Y isnitrogen or R²⁰C; Z is nitrogen or R²¹C; T is nitrogen or R²C; S isnitrogen or R³C;  provided that two of S, T, Y, and Z are nitrogen; R²⁰is selected from hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl,cyano, nitro, C₁₋₅ haloalkyl, R^(o)R^(p)N, R^(o)R^(p)NC═O, C₂₋₈ acyl,4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C₁₋₅ alkylene,phenyl, (phenyl)C₁₋₅ alkylene, R¹⁴OC═O, R¹⁴S, R¹⁴SO, and R¹⁴SO₂; R²¹ isselected from hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl,cyano, nitro, C₁₋₅ haloalkyl, R^(c)R^(d)N, R^(c)R^(d)NC═O, C₂₋₈ acyl,4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C₁₋₅ alkylene,phenyl, (phenyl)C₁₋₅ alkylene, R¹⁵OC═O, R¹⁵S, R¹⁵SO and R¹⁵SO₂; R² isselected from hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl,cyano, nitro, C₁₋₅ haloalkyl, R^(e)R^(f)N, R^(e)R^(f)NC═O, C₂₋₈ acyl,4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C₁₋₅ alkylene,phenyl, (phenyl)C₁₋₅ alkylene, R¹⁶OC═O, R¹⁶S, R¹⁶SO and R¹⁶SO₂; R³ isselected from hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl,cyano, nitro, C₁₋₅ haloalkyl, R^(g)R^(h)N, C₂₋₈ acyl, 4-7 memberedheterocyclyl, (4-7 membered heterocyclyl)-C₁₋₅ alkylene, phenyl,(phenyl)C₁₋₅ alkylene, R¹⁷OC═O, R^(m)R^(n)NC═O, R^(m)R^(n)NSO₂, R¹⁷S,R¹⁷SO and R¹⁷SO₂; R⁵ and R⁶ are independently selected from hydrogen andC₁₋₅ alkyl; R⁷ and R⁸ independently are hydrogen, C₁₋₅ alkyl, C₁₋₅alkenyl, C₁₋₅ alkoxy, C₁₋₅ alkylthio, halogen, or 4-7 memberedcarbocyclyl or heterocyclyl; alternatively, R⁷ and R⁸ can be takentogether to form an optionally substituted 5- to 7-membered carbocyclicor heterocyclic ring, which ring may be unsaturated or aromatic; saidring being optionally substituted with between 1 and 3 substituentsindependently selected from halo, hydroxy, cyano, nitro, amino, R^(t),R^(t)O—, R^(t)S—, R^(t)O(C₁₋₅ alkylene)-, R^(t)O(C═O)—, R^(t)(C═O)—,R^(t)(C═S)—, R^(t)(C═O)O—, R^(t)O(C═O)(C═O)—, R^(t)SO₂, NHR^(u)(C═NH)—,NHR^(u)SO₂—, and NHR^(u)(C═O)—; R^(t) is C₁₋₆ alkyl, phenyl, benzyl,phenethyl, or C₂₋₅ heterocyclyl, (C₁₋₅ heterocyclyl)C₁₋₆ alkylene, NH₂,mono- or di(C₁₋₆ alkyl)N—, or R⁴⁹OR⁵⁰—, wherein R⁴⁹ is H, C₁₋₅ alkyl,C₂₋₅ alkenyl, phenyl, benzyl, phenethyl, C₁₋₅ heterocyclyl, or (C₁₋₅heterocyclyl)C₁₋₆ alkylene and R⁵⁰ is C₁₋₅ alkylene, phenylene, ordivalent C₁₋₅ heterocyclyl; and R^(u) can be H in addition to the valuesfor R^(t); R^(c) is hydrogen, C₁₋₅ alkyl, phenyl, C₂₋₅ heterocyclyl,C₂₋₈ acyl, aroyl, R¹⁰OC═O—, R^(i)R^(j)NC═O, R¹⁰SO—, R¹⁰SO₂—, andR^(i)R^(j)NSO₂; R^(e) is hydrogen, C₁₋₅ alkyl, phenyl, C₂₋₅heterocyclyl, C₂₋₈ acyl, aroyl, R⁴⁰OC═O, R⁴³R⁴⁴NC═O, R⁴⁰SO, R⁴¹SO₂, andR⁴³R⁴⁴NSO₂; R^(m) is hydrogen, C₁₋₅ alkyl, phenyl, C₂₋₅ heterocyclyl,C₂₋₈ acyl, aroyl, R⁴¹OC═O, R⁴⁵R⁴⁶NC═O, R⁴¹SO, R⁴¹SO₂, and R⁴⁵R⁴⁶NSO₂;R^(o) is hydrogen, C₁₋₅ alkyl, phenyl, C₂₋₅ heterocyclyl, C₂₋₈ acyl,aroyl, R⁴²OC═O, R⁴⁷R⁴⁸NC═O, R⁴²SO, R⁴²SO₂, and R⁴⁷R⁴⁸ NSO₂; each ofR^(d), R^(f), R^(n), and R^(p) is independently selected from hydrogen,C₁₋₅ alkyl, phenyl, and C₂₋₅ heterocyclyl; in addition, R^(c) and R^(d),R^(e) and R^(f), R^(m) and R^(n), or R^(o) and R^(p), independently, canbe taken together to form an optionally substituted 4- to 7-memberedheterocyclic ring, which ring may be saturated, unsaturated or aromatic;each of R⁹, R¹⁰, R¹¹, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R⁴⁰, R⁴¹, and R⁴² isindependently C₁₋₅ alkyl, phenyl, or C₂₋₅ heterocyclyl; each of R^(i)and R^(j), R^(k) and R¹, R⁴³ and R⁴⁴, R⁴⁵ and R⁴⁶, R⁴⁷ and R⁴⁸ areindependently hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, or C₂₋₅heterocyclyl; in addition, R^(i) and R^(j), and R^(k) and R^(l), R⁴³ andR⁴⁴, R⁴⁵ and R⁴⁶, and R⁴⁷ and R⁴⁸, independently, can be taken togetherto form an optionally substituted 4- to 7-membered heterocyclic ring,which ring may be saturated, unsaturated or aromatic; R^(g) is hydrogen,C₁₋₅ alkyl, phenyl, or C₂₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R⁹OC═O,R¹⁸R¹⁹NC═O, R⁹SO, R⁹SO₂, or R¹⁸R¹⁹NSO₂; R^(h) is hydrogen, C₁₋₅ alkyl,phenyl, or C₂₋₅ heterocyclyl; alternatively, R^(g) and R^(h) can betaken together to form an optionally substituted 4- to 7-memberedheterocyclic ring, which ring may be saturated, unsaturated or aromatic;R¹⁸ and R¹⁹ independently are hydrogen, C₁₋₅ alkyl, phenyl, or C₂₋₅heterocyclyl;  alternatively, R¹⁸ and R¹⁹ can be taken together to forman optionally substituted 4- to 7-membered heterocyclic ring, which ringmay be saturated, unsaturated or aromatic; n is 0, 1 or 2; G is C₃₋₆alkenediyl or C₃₋₆ alkanediyl, optionally substituted with hydroxy,halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, oxo, hydroximino, CO₂R^(k),NR^(k)R^(l), (L)—C₁₋₄ alkylene-, R^(k)R^(l)NCO₂, [(L)—C₁₋₅alkylene]amino, N₃, or (L)—C₁₋₅ alkoxy; L is amino, mono- or di-C₁₋₅alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, orpiperazinyl, wherein available ring nitrogens can be optionallysubstituted with C₁₋₅ alkyl, benzyl, C₂₋₅ acyl, C₁₋₅ alkylsulfonyl, orC₁₋₅ alkoxycarbonyl; Ar represents a monocyclic or bicyclic aryl orheteroaryl ring, optionally substituted with between 1 and 3substituents independently selected from halogen, C₁₋₅ alkoxy, C₁₋₅alkyl, C₂₋₅ alkenyl, cyano, azido, nitro, R²²R²³N, R²²S, R²²SO, R²²SO₂,R²²OC═O, R²²R²³NC═O, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, C₁₋₅haloalkylthio, and C₁₋₅ alkylthio; R²² is hydrogen, C₁₋₅ alkyl, C₃₋₅alkenyl, phenyl, benzyl, C₂₋₅ heterocyclyl, C₂-8 acyl, aroyl, R¹¹OC═O,R²⁴R²⁵NC═O, R¹¹S, R¹¹SO, R¹¹SO₂, or R²⁴R²⁵NSO₂; R²³ is hydrogen, C₁₋₅alkyl, phenyl, benzyl, or C₂₋₅ heterocyclyl;  alternatively, R²² and R²³can be taken together to form an optionally substituted 4- to 7-memberedheterocyclic ring, which ring may be saturated, unsaturated or aromatic;R²⁴ and R²⁵ are independently hydrogen, C₁₋₅ alkyl, phenyl, benzyl, orC₁₋₅ heteroaryl;  alternatively, R²⁴ and R²⁵ can be taken together toform an optionally substituted 4- to 7-membered carbocyclic orheterocyclic ring, which ring may be saturated, unsaturated or aromatic;R³² is hydrogen, C₁₋₅ alkyl, cyano, C₁₋₅ hydroxyalkyl, C₂₋₈ acyl,—(C═O)NR^(v)R^(x), CHO, or C₁₋₆ alkoxycarbonyl, wherein each of R^(v)and R^(x) is independently selected from H, C₁₋₅ alkyl, C₁₋₅hydroxyalkyl, C₁₋₅ heterocyclyl, (C₁₋₅ heterocyclyl) C₁₋₅ alkylene, C₁₋₅aminoalkylene, C₃₋₈ acyloxy, CHO, C₁₋₆ alkoxycarbonyl, and cyano; Q isNR³³, S, or O; R³³ represents hydrogen, C₁₋₅ alkyl, phenyl, benzyl,phenethyl, C₂₋₅ heterocyclyl, (C₂₋₅ heterocyclyl)C₁₋₅ alkylene, C₂₋₈acyl, aroyl, R³⁵OC═O, R³⁶R³⁷NC═O, R³⁵SO, R³⁵S, R³⁵SO₂ and R³⁶R³⁷NSO₂;R³⁵ is selected from hydrogen, C₁₋₅ alkyl, phenyl, benzyl, phenethyl,and C₂₋₅ heteroaryl; R³⁶ and R³⁷ are each independently selected fromhydrogen, C₁₋₅ alkyl, phenyl, or C₂₋₅ heteroaryl;  alternatively, R³⁶and R³⁷ can be taken together to form an optionally substituted 4- to7-membered ring heterocyclic ring, which ring may be saturated,unsaturated or aromatic; wherein each of the above hydrocarbyl orheterocarbyl groups, unless otherwise indicated, and in addition to anyspecified substituents, is optionally and independently substituted withbetween 1 and 3 substituents selected from methyl, halomethyl,hydroxymethyl, halo, hydroxy, amino, nitro, cyano, C₁₋₅ alkyl, C₁₋₅alkoxy, —COOH, C₂₋₆ acyl, [di(C₁₋₄ alkyl)amino]C₂₋₅ alkylene, [di(C₁₋₄alkyl)amino] C₂₋₅ alkyl-NH—CO—, and C₁₋₅ haloalkoxy; or apharmaceutically acceptable salt, amide, or ester thereof; or astereoisomeric form thereof.
 2. A compound of claim 1, wherein one of Yand Z are CR²⁰ and CR²¹, respectively.
 3. A compound of claim 1, whereinS and T are CR³ and CR², respectively.
 4. A compound of claim 1, whereinS is N, T is N, Y is CR²⁰, and Z is CR²¹.
 5. A compound of claim 1,wherein Z is N, Y is N, S is CR³, and T is CR².
 6. A compound of claim1, wherein R is hydrogen, halogen, C₁₋₅ alkoxy, cyano, R^(e)R^(f)N, or a5-6 membered heterocyclyl.
 7. A compound of claim 1, wherein R³ ishydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano, R¹⁷OC═O, orR^(g)R^(h)N, where R^(g) and R^(h) are H or C₁₋₅ alkyl, or are takentogether to form a 5-6 membered heterocyclyl.
 8. A compound of claim 1,wherein each of R² and R³ is independently selected from hydrogen,halogen, and a 5-6 membered heterocyclyl.
 9. A compound of claim 1,wherein R⁵ and R⁶ are independently selected from hydrogen and C₁₋₃alkyl.
 10. A compound of claim 9, wherein one of R⁵ and R⁶ is H.
 11. Acompound of claim 10, wherein R⁵ and R⁶ are each H.
 12. A compound ofclaim 1, wherein one of R⁷ and R⁸ is H and the other is 5-7 memberedcarbocyclyl or heterocyclyl.
 13. A compound of claim 1, wherein R⁷ andR⁸ are taken together to form an optionally substituted 5- to 7-memberedcarbocyclic or heterocyclic ring.
 14. A compound of claim 13, wherein R⁷and R⁸ are taken together to form a six-membered heterocyclyl.
 15. Acompound of claim 13 wherein R⁷ and R⁸ taken together form a 5-7membered heterocyclyl optionally N-substituted with R^(t)(C═O)—,R^(t)SO₂—, or NHR^(u)(C═O)— wherein R^(t) is C₁₋₆ alkyl, phenyl, or C₂₋₅heterocyclyl and R^(u) is H, C₁₋₆ alkyl, phenyl, or C₂₋₅ heterocyclyl.16. A compound of claim 1, wherein each of R^(c), R^(e), R^(m), andR^(o) is independently selected from hydrogen, C₁₋₅ alkyl, C₂₋₈ acyl,(C₁₋₅ alkyl)OC═O, and the respective RRNC═O, RSO, RSO₂, and RRNSO₂groups.
 17. A compound of claim 1, wherein each of R^(c), R^(d), R^(g),R^(h), R^(o), R^(f), and R^(p) is independently selected from hydrogenand C₁₋₅ alkyl; or, independently, R^(e) and R^(f), R^(g) and R^(h), orR^(o) and R^(p) taken together form an optionally substituted 4- to7-membered carbocyclic or heterocyclic ring.
 18. A compound of claim 17wherein R^(e) and R^(f) taken together are morpholinyl, piperidinyl, orpyrrolidinyl.
 19. A compound of claim 1, wherein each of R⁴³, R⁴⁴, R⁴⁵,R⁴⁶, R⁴⁷, R⁴⁸, R^(i), R^(j), R^(k) and R^(l) independently is hydrogenor C₁₋₅ alkyl.
 20. A compound of claim 1, wherein each of R⁹, R¹¹, R¹⁴,R¹⁵, R¹⁶ and R¹⁷ is independently C₁₋₅ alkyl.
 21. A compound of claim 1,wherein R^(g) is C₁₋₅ alkyl, C₂₋₈ acyl, R⁹OC═O, R¹⁸R¹⁹NC═O, R⁹SO, R⁹SO₂,or R¹⁸R¹⁹NSO₂; and R^(h) is H or C₁₋₅ alkyl; alternatively, R^(g) andR^(h) can be taken together to form an optionally substituted 5- to6-membered heterocyclyl.
 22. A compound of claim 21, wherein R^(g) andR^(h) are each C₁₋₃ alkyl.
 23. A compound of claim 1, wherein R¹⁸ andR¹⁹ independently are hydrogen or C₁₋₅ alkyl.
 24. A compound of claim 1,wherein n is
 1. 25. A compound of claim 1, wherein G is C₃₋₄ alkanediyl,optionally substituted with hydroxy, halogen, [(L)—C₁₋₅ alkylene]amino,or (L)—C₁₋₅ alkyloxy.
 26. A compound of claim 25, wherein G is C₃alkanediyl, optionally substituted with hydroxy.
 27. A compound of claim1, wherein R²⁰ and R²¹ are independently selected from hydrogen,halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano, nitro, 4-7 memberedheterocyclyl, and R^(o)R^(p)N or R^(c)R^(d)N, respectively.
 28. Acompound of claim 27, wherein R²⁰ and R²¹ are independently selectedfrom hydrogen, halogen, 5- to 6-membered heterocyclyl, and R^(o)R^(p)Nor R^(c)R^(d)N, respectively.
 29. A compound of claim 1, wherein Arrepresents a monocyclic ring, optionally substituted with 1 to 2substituents selected from halogen, C₁₋₅ alkyl, cyano, nitro, R²²R²³N,C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy.
 30. A compound of claim 29, whereinAr is a six-membered aromatic ring monosubstituted at the 4-positionwith halogen, methyl, CF₃, or OCF₃, or disubstituted at the 3- and4-positions with substituents independently selected from halogen, CF₃,methyl, and OCF₃.
 31. A compound of claim 29, wherein each of R²², R²³,and R²⁴ is independently hydrogen or C₁₋₅ alkyl.
 32. A compound of claim1, wherein R²⁵ and R²⁶ independently are hydrogen or C₁₋₅ alkyl, or,alternatively, R²⁵ and R²⁶ are taken together to form an optionallysubstituted 4- to 7-membered heterocyclic ring, which ring may besaturated, unsaturated or aromatic.
 33. A compound of claim 32, whereinR²⁵ and R²⁶ independently are hydrogen or C₁₋₅ alkyl.
 34. A compound ofclaim 1, wherein Q is NR³³ or S.
 35. A compound of claim 34, wherein Qis NR³³, R³³ is H or C₂₋₅ heterocyclyl, and R³² is H, C₁₋₅ alkyl, C₁₋₅hydroxyalkyl, —(C═O)NR^(v)R^(x), CHO, or C₁₋₆ alkoxycarbonyl, whereineach of R^(v) and R^(x) is independently selected from H, C₁₋₅hydroxyalkyl, (C₁₋₅ heterocyclyl)-C₁₋₅ alkylene, and C₁₋₅ aminoalkylene.36. A compound of claim 34, wherein Q is S and R³³ is NR³⁶R³⁷(C═O)—where each of R³⁶ and R³⁷ are independently selected from hydrogen andC₁₋₅ alkyl.
 37. A compound of claim 1, wherein R³⁵ is selected fromhydrogen and C₁₋₅ alkyl; R³⁶ and R³⁷ are each independently selectedfrom hydrogen, C₁₋₅ alkyl, or, alternatively, R³⁶ and R³⁷ can be takentogether to form an optionally substituted 4- to 7-membered heterocyclicring.
 38. A compound of claim 1, wherein Y is nitrogen or R²⁰C; Z isnitrogen or R²¹C; T is nitrogen or R²C; S is nitrogen or R³C; providedthat two of S, T, Y, and Z are nitrogen; R² is hydrogen, halogen,hydroxy, C₁₋₅ alkoxy, C₁₋₅ alkyl, 5- to 6-membered heterocyclyl, orR^(e)R^(f)N; R³ is hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl,5- to 6-membered heterocyclyl, or R^(g)R^(h)N; R⁵ and R⁶ are each H; R⁷and R⁸ independently are taken together to form an optionallysubstituted 5- to 7-membered unsaturated heterocyclic ring; each ofR^(a), R^(e), R^(m), and R^(o) is independently selected from hydrogen,C₁₋₅ alkyl, C₂₋₈ acyl, (C₁₋₅ alkyl)OC═O, and the respective RRNC═O, RSO,RSO₂, and RRNSO₂ groups; each of R^(b), R^(f), R^(n), and R^(p), isindependently selected from hydrogen and C₁₋₅ alkyl; each of R⁹, R¹¹,R¹⁴, R¹⁵, R¹⁶, R¹⁷, R⁴⁰, R⁴¹ and R⁴² is independently C₁₋₅ alkyl; eachof R^(c), R^(d), R^(i), R^(j), R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R^(k) and R^(l)are independently are hydrogen or C₁₋₅ alkyl; R^(g) is hydrogen, or C₁₋₅alkyl, C₂₋₈ acyl, R⁹OC═O, R¹⁸R¹⁹NC═O, R⁹SO, R⁹SO₂, or R¹⁸R¹⁹NSO₂; R^(h)is hydrogen or C₁₋₅ alkyl;  alternatively, R^(g) and R^(h) can be takentogether to form an optionally. substituted 4- to 7-membered carbocyclicor heterocyclic ring, which ring may be saturated, unsaturated oraromatic; R¹⁸ and R¹⁹ independently are hydrogen or C₁₋₅ alkyl; n is 0or 1; G is C₃₋₄ alkenediyl or C₃₋₄ alkanediyl, optionally substitutedwith hydroxy, halogen, C₁₋₅ alkyloxy, oxo, hydroximino, CO₂R^(k),R^(k)R^(l)NCO₂, N₃, or (L)-C₁₋₅ alkoxy; L is amino, mono- or di-C₁₋₅alkylamino, pyrrolidinyl, morpholinyl, piperidinyl homopiperidinyl, orpiperazinyl, available ring nitrogens being optionally with C₁₋₅ alkyl,benzyl, C₂₋₅ acyl, or C₁₋₅ alkyloxycarbonyl; R²⁰ and R²¹ areindependently selected from hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl,cyano, nitro, and R^(o)R^(p)N; alternatively, R³ and R²⁰ or R³ and R²¹can be taken together to form an optionally substituted 5- or 6-memberedcarbocyclic or heterocyclic ring, which ring may be saturated,unsaturated or aromatic; Ar represents a monocyclic or bicyclic aryl orheteroaryl ring, optionally substituted with hydrogen, halogen, C₁₋₅alkoxy, C₁₋₅ alkyl, cyano, nitro, R²²R²³N, R²⁴SO₂, R²⁴OC═O, R²⁵R²⁶NC═O,CF₃, OCF₃, SCF₃, or C₁₋₅ alkylthio; R²² is hydrogen, C₁₋₅ alkyl, phenyl,benzyl, phenethyl, C₂₋₅ heteroaryl, C₂₋₈ acyl, aroyl, R²⁴OC═O,R²⁵R²⁶NC═O, R²⁴SO, R²⁴SO₂, or R²⁵R²⁶NSO₂; R²³ is hydrogen or C₁₋₅ alkyl;alternatively, R²² and R²³ can be taken together to form an optionallysubstituted 4- to 7-membered carbocyclic or heterocyclic ring, whichring may be saturated, unsaturated or aromatic; R²⁴ is hydrogen or C₁₋₅alkyl; R²⁵ and R²⁶ are independently hydrogen or C₁₋₅ alkyl; or,alternatively, R²⁵ and R²⁶ can be taken together to form an optionallysubstituted 4- to 7-membered carbocyclic or heterocyclic ring, whichring may be saturated, unsaturated or aromatic; R³² is hydrogen, C₁₋₅alkyl, C₁₋₅ hydroxyalkyl, CHO, C₂₋₆ acyl, C₁₋₆ alkoxycarbonyl, or—(C═O)NR^(v)R^(x), wherein each of R^(v) R^(x) is independently selectedfrom H, C₁₋₅ alkyl, C₁₋₅ hydroxyalkyl, C₃₋₈ acyloxy, (amino)C₁₋₆alkylene, (C₁₋₅ heterocyclyl)C₁₋₅ alkylene, or C₁₋₆ alkoxycarbonyl; Q isNR³³ or S; R³³ represents hydrogen, C₁₋₅ alkyl, phenyl, benzyl, (C₂₋₅heterocyclyl)C₁₋₅ alkylene, C₂₋₈ acyl, aroyl, R³⁵OC═O, R³⁶R³⁷NC═O,R³⁵SO₂ and R³⁶R³⁷NSO₂; R³⁵ is selected from hydrogen and C₁₋₅ alkyl; R³⁶and R³⁷ are each independently selected from hydrogen and C₁₋₅ alkyl.39. A compound of claim 1, wherein one of R⁵ and R⁶ is H, R⁷ and R⁸ aretaken together to form an optionally substituted 6-membered carbocyclicor heterocyclic ring; and Ar represents a monocyclic ring, optionallysubstituted with 1 to 2 substituents selected from halogen, C₁₋₅ alkyl,cyano, nitro, R²²R²³N, CF₃ and OCF₃.
 40. A compound of claim 39, whereinboth R⁵ and R⁶ are each H, and Ar is a six membered ring substitutedwith halogen, CF₃, methyl, halomethyl, or OCF₃, at the 3- or 4-position,or disubstituted at the 3- and 4-positions.
 41. A compound of claim 40,wherein R⁷ and R⁸ taken together form pyridinyl, pyrimidinyl, orpiperazinyl, optionally N-substituted with —(C═O)R^(t), SO₂—R^(t), or—(C═O)NHR^(u).
 42. A compound of claim 39, wherein R²² and R²³ takentogether are independently morpholinyl, piperidyl, or pyrrolidinyl,optionally substituted.
 43. A compound of claim 1, wherein the dashedline adjacent C—R⁶ is absent.
 44. A pharmaceutical composition,comprising a compound of claim 1 or 38, and a pharmaceuticallyacceptable carrier.
 45. A method for treating a subject with a conditionmediated by cathepsin S, said method comprising administering to thesubject a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of claim 1 or
 38. 46. A method forinhibiting cathepsin S activity in a subject, said method comprisingadministering to the subject a therapeutically effective amount of apharmaceutical composition comprising a compound of claim 1 or
 27. 47. Amethod for treating an autoimmune disease, or inhibiting the progressionof an autoimmune disease, in a subject, said method comprisingadministering to the subject a therapeutically effective amount of apharmaceutical composition comprising a compound of claim 1 or
 27. 48. Amethod of claim 47, wherein the autoimmune disease is selected fromlupus, rheumatoid arthritis, and asthma.
 49. A method of claim 47,wherein the autoimmune disease is asthma.
 50. A method for treating orinhibiting the progression of tissue transplant rejection in a subject,said method comprising administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition comprising a compoundof claim 1 or
 27. 51. A method of claim 50, wherein said administrationoccurs after said subject has undergone a tissue transplant procedure.52. A method of claim 50, wherein said administration to said subjectoccurs before or during a tissue transplant procedure.